Vol. 18, No. 24, July 14, 1989 NOTICES MANDATORY USE OF LATEST FELLOWSHIP APPLICATION KITS ........(84/95).......... 1 Division of Research Grants Index: DIVISION OF RESEARCH GRANTS AVAILABILITY OF FISH OIL TEST MATERIALS ....................(98/253)......... 1 National Institutes of Health Index: NATIONAL INSTITUTES OF HEALTH DATED ANNOUNCEMENTS (RFPs AND RFAs) HUMAN IMMUNODEFICIENCY VIRUS INHIBITORY FACTORS IN HUMAN SALIVA (RFA)........ 3 National Institute of Dental Research (259/419) Index: DENTAL RESEARCH DEVELOPMENT AND CHARACTERIZATION OF IMMORTALIZED SALIVARY GLAND EPITHELIAL CELL LINES (RFA) ...........................(422/462, 724/1031)... 5 National Institute of Dental Research Index: DENTAL RESEARCH ENVIRONMENTAL FACTORS PREDISPOSING TO THE ACQUISITION OF DRUG ABUSE (RFA) ...........................................(465/569)............. 5 National Institute on Drug Abuse Index: DRUG ABUSE INTERVENTIONS FOR CONTROL OF ASTHMA AMONG BLACK AND HISPANIC CHILDREN (RFA) ........................................(1034/1404)........... 7 National Heart, Lung, and Blood Institute Index: HEART, LUNG, AND BLOOD NOTICES MANDATORY USE OF LATEST FELLOWSHIP APPLICATION KITS P.T. 22; K.W. 0720005, 1014006 Division of Research Grants Beginning with the September 10, 1989, receipt deadline, all applicants for the individual postdoctoral fellowship (F32) or senior fellowship (F33) must use the latest application kits (PHS 416-1, Revised 7/88 or 4/89). Only the 7/88 and 4/89 revisions are acceptable. Submissions on earlier versions of the PHS 416-1 are incompatible with new procedures for the expedited review of fellowship applications and will be returned without review. AVAILABILITY OF FISH OIL TEST MATERIALS P.T. 34; K.W. 0780005 National Institutes of Health SUMMARY AND PURPOSE FISH OIL TEST MATERIALS PROGRAM The Fish Oil Test Materials Program was established in 1986 through the cooperation of the National Institutes of Health (NIH), the Alcohol, Drug Abuse, and Mental Health Administration (ADAMHA), and the National Oceanic and Atmospheric Administration/Department of Commerce (NOAA/DOC). This program, which is administered by the Division of Nutrition Research Coordination in the Office of Disease Prevention, NIH, was designed to provide a long-term, consistent supply of quality-assured/quality-controlled test materials to researchers in order to facilitate the evaluation of the role that omega-3 fatty acids play in health and disease. Fish Oil Test Materials Advisory Committee: The Fish Oil Test Materials Advisory Committee (FOTMAC) is cochaired by scientific staff from ADAMHA and NIH and is composed of scientists representing the funding agencies (NIH, ADAMHA), the research community, the Department of Commerce (DOC) and the Food and Drug Administration (FDA). The FOTMAC provides scientific advice to the DOC regarding the types of materials needed by research scientists, shipping procedures for the materials, and additional quality control and production issues. The committee is advisory to the Fish Oil Test Materials Program on general programmatic issues, such as future directions, and has produced a Good Lab Practices for Polyunsaturate Handling Manual. In addition, the committee provided guidance to DOC during the production of the Drug Master File that was submitted to the FDA by the FOTMAC. A manual on Analytical Methods for the Quality Assurance of Fish Oil was produced by the DOC. Fish Oil Test Materials Distribution Committee: A Fish Oil Test Materials Distribution Committee (FOTMDC) is composed of NIH and other Federal scientists that do not use these products. The Distribution committee processes the applications received from investigators, advises the DOC of applications that have fulfilled the application requirements, and makes recommendations regarding the distribution of requested materials. The awarded materials are provided to investigators free of charge. Availability of materials are contingent on DOC/NOAA production capabilities. When prioritization is necessary, the order will be: 1) NIH/ADAMHA funded, 2) other government funded, 3) peer-reviewed, privately funded, 4) NIH/ADAMHA approved, not funded, and 5) other. REQUIREMENTS To qualify to receive materials described in this announcement, the applicant must: 1) be engaged in peer-reviewed research, and 2) submit a correctly completed application form and a signed waiver of liability. The committee will not be responsible for assessing the scientific merit of the application. Regulations on human subjects and animal research apply. In accordance with federal regulations, an IND number will be required for the use of these materials in human studies. The FOTMAC has established a drug master file at the FDA that includes manufacturing, chemical composition, and toxicological Vol. 18, No. 24, July 14, 1989 - Page 1 data relevant to these products. Investigators using DOC/NOAA materials may reference this file in order to expedite their IND requests. TEST MATERIALS CURRENTLY AVAILABLE o n-3 ethyl ester concentrate, prepared from menhaden oil, bulk packed or soft-gel encapsulated (80 percent n-3 fatty acids including EPA and DHA) o Ethyl esters of olive oil (70 percent oleic), bulk packed or soft-gel encapsulated o Deodorized menhaden oil, bulk packed or soft-gel encapsulated o Commercial preparations of corn, olive, or safflower oil, soft-gel encapsulated only PROCESSING AND SPECIFICATIONS OF BIOMEDICAL TEST MATERIALS o n-3 Ethyl Ester Concentrate The n-3 ethyl ester concentrate is prepared from vacuum-deodorized menhaden oil using transesterification, urea adduction and short-path distillation. The concentrate contains approximately 80 percent n-3 fatty acid ethyl esters (44 percent EPA, 24 percent DHA, 10-12 percent other n-3 fatty acid ethyl esters), 3 percent C18 (other than n-3), 6 percent C16 and the remainder as other esters. It contains 0.2 mg/g TBHQ as antioxidant, 2 mg/g tocopherols and 2.0 mg/g cholesterol. The concentrate is available in 1 g soft-gel capsules (100 capsules/bottle) or packaged in bulk in quantities suitable to investigators needs. o Placebo Ethyl Esters The ethyl esters of virgin olive oil are prepared by transesterification. The preparation contains approximately 70 percent oleic acid, 13 percent C16, and 15 percent C18 (<1 percent n-3) fatty acid ethyl esters. It contains 0.2 mg/g TBHQ as antioxidant and 2 mg/g tocopherols. The preparation is available in 1 g soft-gel capsules (100 capsules/bottle) or packaged in bulk in quantities suitable to investigators needs. o Deodorized Menhaden Oil Deodorized menhaden oil is prepared from oil that has been winterized and alkali refined; it is processed through a two-stage wiped-film evaporator to remove cholesterol, volatile oxidation products, and any traces of organic contaminants. The oil contains approximately 30 percent n-3 fatty acids in the triglyceride form; 14 percent EPA, 8 percent DHA, 8 percent other n-3. It contains 0.2 mg/g TBHQ as antioxidant, 2 mg/g tocopherols, and 2.0 mg/g cholesterol. The deodorized oil is available in 1 g soft-gel capsules (100 capsules/bottle) or in bulk quantities suitable to investigators needs. Special requests for antioxidant-free oil will be considered. o Placebo Oils Commercial preparations of corn, olive, and safflower oil have been soft-gel encapsulated to serve as placebos for studies involving encapsulated menhaden oil. These oils contain 0.2 mg/g TBHQ as antioxidant and 2 mg/g tocopherols. The major fatty acids for each oil are: corn (58 percent 18:2n-6, 26 percent 18:1n-9), olive (17 percent 18:2n-6, 57 percent 18:1n-9), safflower (80 percent 18:2n-6, 9 percent 18:1n-9). They are available in 1 g soft-gel capsules (100 capsules/bottle). Although vegetable oils will not be supplied in bulk form, investigators may request analysis of antioxidant and tocopherol levels in vegetable oils that they purchase. Test Materials Available in the Future: Test materials and the relevant application process will be announced in the NIH Guide for Grants and Contracts as new materials become available. Other Information: The investigator will be provided with complete quality assurance data for each lot of test material shipped, general diet preparation information, and instructions for formulation of placebos containing antioxidants balanced to the level in the test material. Vol. 18, No. 24, July 14, 1989 - Page 2 INQUIRIES AND APPLICATIONS Investigators may obtain further information on available fish oil test materials and request an application form from: Ms. Melissa Workman Program Assistant Fish Oil Test Materials Program Division of Nutrition Research Coordination Building 31, Room 4B63 National Institutes of Health Bethesda, Maryland 20892 Telephone: (301) 496-2323 DATED ANNOUNCEMENTS (RFPs AND RFAs) HUMAN IMMUNODEFICIENCY VIRUS INHIBITORY FACTORS IN HUMAN SALIVA RFA AVAILABLE: 89-DE-2 P.T. 34; K.W. 0715008, 0760035, 1002045 National Institute of Dental Research Application Receipt Date: November 10, 1989 INTRODUCTION The Periodontal and Soft Tissue Diseases Branch of the Extramural Programs of the National Institute of Dental Research (NIDR) invites project grant applications to study salivary inhibition of human immunodeficiency virus (HIV) infectivity. In view of recently reported preliminary findings indicating that human saliva exhibits HIV-inhibitory activity (1-3) the NIDR is soliciting applications to verify and amplify these initial findings, to begin studies to isolate, identify, and characterize active factors, and to determine their mechanisms of action. This Request for Applications (RFA) is for a single competition with a receipt deadline of November 10, l989. Applications should be prepared and submitted in accordance with the aims and requirements outlined below. Additional information may be obtained from the scientist administrators identified in the section APPLICATION AND REVIEW PROCEDURES below. BACKGROUND Despite the frequency and severity of oral lesions associated with HIV infection and AIDS, and the presence of HIV in gingival crevice fluid, recent studies indicate that HIV is detected only infrequently in human saliva. Since it is likely that the oral tissues of high risk individuals are repeatedly exposed to the virus, it was proposed that human saliva might contain factors inhibitory to HIV. Subsequently, initial findings were made in approximately 35 individuals, indicating that HIV-inhibitory activity may be present in whole saliva and in submandibular/sublingual saliva from HIV-seronegative men, women and children and from seropositive men. These experiments suggest that the inhibitory activity is due to salivary components which may coaggregate nonspecifically with the virus or with HIV-infected macrophages to form complexes that have the effect of isolating the virus from susceptible tissue cells. Another possibility is that proteolytic activity in the saliva may damage or destroy HIV directly, or degrade the reverse transcriptase enzyme, which is the basis for assaying the virus. Inhibition could also occur by the blockage of specific mechanisms involved in the infective process. RESEARCH GOALS Although the evidence for inhibitory factors is not conclusive, it is sufficiently provocative to warrant accelerated efforts to verify and amplify the initial findings, to begin efforts to isolate, identify, purify and characterize them, and to clarify their mechanisms of action, whether they involve salivary effects on the virus itself or on virus-containing macrophages. It is envisioned that studies funded from this RFA will require the joint collaborative efforts of a competent virologist and an expert salivary biochemist. An expert in the immunology of oral secretions may also be needed. Proposed studies may focus on human saliva from normal, Vol. 18, No. 24, July 14, 1989 - Page 3 non-HIV-infected individuals (seronegative) or from HIV-seropositive individuals without signs and symptoms of AIDS. The NIDR anticipates funding meritorious proposals resulting from this RFA as early as March 1, l990. To expedite the dissemination and exploitation of new data resulting from these studies, NIDR requests that investigators funded from this RFA provide written progress reports at six-month intervals. These reports should be submitted to Dr. Rizzo at the address given in the section APPLICATION AND REVIEW PROCEDURES below. 1. Fultz, P.N. Components of saliva inactivate human immunodeficiency virus. Lancet ii:1215, 1986. 2. Fox, P.C., Wolff, A., Yeh, C-K., Atkinson, J.C., and Baum, B.J. Saliva inhibits HIV-1 infectivity. JADA 116:635, 1988. 3. Fox, P.C., Wolff, A., Yeh, C-K., Atkinson, J.C., and Baum, B.J. Saliva inhibition of HIV-1 infectivity: Functional properties and distribution in men, women and children. JADA In press, June 1989. MECHANISM OF SUPPORT Awards will be made as regular research project grants (R01). Applicants may request up to 3 years of support. Subsequent support in this research area will be dependent upon submission by the applicant of a renewal application through established NIH procedures for research grants related to AIDS. Policies that govern research grant programs of the National Institutes of Health will prevail. The NIDR will allocate funds to support projects from this RFA during 1990-1992; however, such awards are contingent upon receipt of appropriated funds. It is anticipated that at least three awards will be made, provided that research plans are of sufficient scientific merit and promise, and involve the appropriate expert collaborators. Applicants are encouraged to consider collaborative arrangements with investigators from other organizations, such as the NIDR and other NIH institutes. APPLICATION AND REVIEW PROCEDURES Applications submitted in response to this RFA will be reviewed for scientific merit by a Special Review Committee convened by the NIDR Scientific Review Branch. Secondary review will be carried out by the National Advisory Dental Research Council. Successful applications will be funded as early as March 1, 1990. Review criteria for the proposals submitted will include the usual considerations made by NIH review groups, as well as special attention to the need for highly specific expertise in retrovirus biology, salivary biochemistry and immunology. Applications should be submitted on form PHS-398 (Rev. 10/88), available in the business or grants office of most academic or research institutions or from the Division of Research Grants, National Institutes of Health. Applications received after November 10, 1989, and those which are deemed nonresponsive to the RFA will be assigned to a Division of Research Grants Study Section for initial review and will be reviewed with other unsolicited grant applications received during that review cycle. To identify the application as a response to this RFA, check "yes" on item 2 of page 1 of the application and enter RFA: 89-DE-2 "Human Immunodeficiency Virus Inhibitory Factors in Human Saliva." The RFA label available in the 10/88 revision of Application Form PHS-398 must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of your application such that it may not reach the review committee in time for review. The original and 22 copies should be received by November 10, 1989, at: Grant Application Receipt Office Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, Maryland 20892-4500** Vol. 18, No. 24, July 14, 1989 - Page 4 Two copies should be sent to: Anthony A. Rizzo, D.M.D. Chief, Periodontal & Soft Tissue Diseases Research Branch National Institute of Dental Research Westwood Building, Room 509 Bethesda, Maryland 20892-4500 Telephone: (301) 496-7784 Inquiries concerning this RFA may be addressed to Dr. Anthony Rizzo or Dr. Matthew Kinnard at (301) 496-7784. This program is described in the Catalog of Federal Assistance No. 13.122. Awards will be made under authorization of the Public Health Service Act, Title III. Section 301 (Public Law 78-410, as amended), and administered under PHS grants policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. DEVELOPMENT AND CHARACTERIZATION OF IMMORTALIZED SALIVARY GLAND EPITHELIAL CELL LINES RFA AVAILABLE: 89-DE-3 P.T. 34; K.W. 0780000, 0780015, 1002058, 0790005 National Institute of Dental Research Application Receipt Date: December 13, 1989 The Caries, Restorative Materials, and Salivary Research Branch of the Extramural Program of the National Institute of Dental Research invites regular research project grant (R01) applications to be considered in a single competition for support of research on the development and functional, structural, and antigenic characterization of immortalized normal human and rodent salivary gland (all types, both major and minor) epithelial (all types, both acinar and ductal) cell lines capable of maintaining the differentiated parental strain phenotype. Establishment of such cell lines would greatly facilitate definitive studies of salivary-specific gene expression in developing and adult glands, molecular mechanisms of salivary gland exocytosis, and regulation of fluid and electrolyte transport. It is anticipated that up to four awards will be made, if a sufficient number of high quality applications is received. The earliest funding date is July 1, 1990. Applications should be prepared and submitted in accordance with the objectives and requirements described in the full RFA, available from: G. G. Roussos, Ph.D. Chief, Caries, Restorative Materials, and Salivary Research Branch National Institute of Dental Research Westwood Building, Room 505 Bethesda, Maryland 20892-4500 Telephone: (301) 496-7884 Awards in response to this announcement will be made to foreign institutions only for research of very unusual merit, need, and promise, and in accordance with Public Health Service policy governing such awards. ENVIRONMENTAL FACTORS PREDISPOSING TO THE ACQUISITION OF DRUG ABUSE RFA AVAILABLE: DA-89-05 P.T. 34; K.W. 0404009, 0411005, 0725000 National Institute on Drug Abuse Application Receipt Dates: February 15, 1990 and May 15, 1990 The National Institute on Drug Abuse (NIDA) invites applications for basic laboratory research on the environmental factors that predispose to the acquisition of drug abuse. Vol. 18, No. 24, July 14, 1989 - Page 5 Purpose After initial use of an abusable drug, individuals vary widely in their subsequent pattern of use. Some, for example, abstain. Others rapidly escalate to the point of compulsive use while others reach that point slowly. Clearly, there are differential risks for drug abuse. The conditions which create these differential outcomes are not well understood. Additional basic experimental research is needed to study the environmental factors that determine the differential outcomes following initial drug use. Research Objectives There is a large and growing body of basic research on the variables which affect drug taking once it is established. However, factors which predispose individuals to the acquisition of drug taking are largely unexplored. Some of the predisposing variables that contribute to the differential risk of drug taking may lie in the individual's past, such as social environment. Other variables may be found in the individual's present environment, including drug-related factors such as dose and route of administration, as well as non-drug factors such as density of other positive reinforcers and presence of aversive contingencies. Laboratory experiments on the acquisition of drug taking and its predisposing variables should yield important information on the variables that facilitate, retard, and prevent drug taking, including answers to questions such as the following: Do variables which generate faster acquisition of drug taking also generate a higher degree of drug taking? Do drugs with high abuse potential in humans generate faster acquisition of drug taking in animals? Are there variables that can produce rapid escalation of drug taking from a low level baseline? Are there predisposing factors essentially the same for all drugs or do different drugs have different predisposing factors? This research should be designed to produce important information for designing prevention strategies as well as intervention strategies. Mechanisms of Support The support mechanism for grants in this area will be the individual research grant (R01), the small grant (R03) and the FIRST award (R29). Applications submitted in response to this RFA will compete for approximately $1.0 million in new grant money expected to be available for this purpose in Fiscal Year 1991. This level of activity is dependent on the receipt of a sufficient number of applications of suitable, scientific merit. Also, the amount of funding available will depend on appropriated funds and program priorities at the time of award. Application and Review Procedures Applications in response to this announcement will be reviewed in accordance with the usual Public Health Service peer review procedures for research grants. Review criteria include the relevance of the proposed research to improving understanding of the basic behavioral factors underlying the development of drug abuse and those that prevent or retard development of drug abuse, and the potential of the research to provide information relevant to improving methods of prevention of drug abuse. Insert the title and number of this RFA, "ENVIRONMENTAL FACTORS PREDISPOSING TO THE ACQUISITION OF DRUG ABUSE" RFA DA-89-05, on line 2 of the face page of the application (PHS 398, rev. 10/88). The RFA label available in the 10/88 revision of the application form PHS 398 must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. For copies of the complete RFA, please contact: Grants Management Branch National Institute on Drug Abuse Parklawn Building, Room 10-25 5600 Fishers Lane Rockville, Maryland 20857 Telephone: (301) 443-6710 Vol. 18, No. 24, July 14, 1989 - Page 6 For information about the program, please contact: Dr. Cora Lee Wetherington Division of Clinical Research National Institute on Drug Abuse Parklawn Building, Room l0A-16 5600 Fishers Lane Rockville, Maryland 20857 Telephone: (301) 443-1263 INTERVENTIONS FOR CONTROL OF ASTHMA AMONG BLACK AND HISPANIC CHILDREN RFA AVAILABLE: 89-HL-11-L P.T. 34, FC, FD; K.W. 0715013, 0795003 National Heart, Lung, and Blood Institute Application Receipt Date: December 1, 1989 The Division of Lung Diseases, National Heart, Lung, and Blood Institute (NHLBI), announces the availability of a Request for Applications (RFA) on the above subject. Copies of the RFA are available from the Division. Awards will not be made to foreign institutions. Asthma is a major public health problem in the United States, affecting 10 million people and resulting in high medical care costs and absenteeism from work or school. However, it is possible, generally through drug treatment and self-management, to achieve adequate control of symptoms. Asthma appears to be an even greater problem among minority populations, especially Blacks than among whites. Asthma deaths have been reported to be three times higher in Blacks in comparison with whites and hospitalization rates for Blacks are twice those of whites. Impediments to achieving control include not having access to continuity of medical care, lack of adherence to treatment regimens, and problems associated with effective self-management. Other associated barriers may include low educational and literacy levels, inadequate housing, and language and other cultural differences between health care providers and patients that may impede effective provider-patient interaction. This program invites grant applications for demonstration and education research projects to develop, implement, and evaluate interventions to achieve long-term control of asthma among Black and Hispanic children. A hypothesis specifically focused on the target population and measurements of changes in health status and health behavior must be included. Funding requests to support existing asthma control programs without a research component or to investigate the effectiveness of clinical therapies would not be considered responsive to this solicitation. This solicitation may be of interest to investigators from a broad range of disciplines such as pulmonary medicine, pediatrics, behavioral sciences, epidemiology, public health, health education, biostatistics, and communication sciences. Multidisciplinary approaches are appropriate. Applicants must demonstrate access to a defined target population of Black and/or Hispanic children, a control or comparison group, and expertise within the proposed research team to carry out research sensitive to the needs of the minority population. It is anticipated that up to four grants, for a maximum of five years each, will be awarded under this program. Requests for copies of the RFA should be addressed to: Joan M. Wolle, Ph.D., M.P.H. Health Scientist Administrator Prevention, Education, and Research Training Branch Division of Lung Diseases Westwood Building, Room 640 5333 Westbard Avenue Bethesda, Maryland 20892 Telephone: (301) 496-7668 Vol. 18, No. 24, July 14, 1989 - Page 7 **THE MAILING ADDRESS GIVEN FOR SENDING APPLICATIONS TO THE DIVISION OF RESEARCH GRANTS OR CONTACTING PROGRAM STAFF IN THE WESTWOOD BUILDING IS THE CENTRAL MAILING ADDRESS FOR THE NATIONAL INSTITUTES OF HEALTH. APPLICANTS WHO USE EXPRESS MAIL OR A COURIER SERVICE ARE ADVISED TO FOLLOW THE CARRIER'S REQUIREMENTS FOR SHOWING A STREET ADDRESS. THE ADDRESS FOR THE WESTWOOD BUILDING IS: 5333 Westbard Avenue Bethesda, Maryland 20816 Vol. 18, No. 24, July 14, 1989 - Page 8 FULL TEXT OF RFAs FOR ONLINE ACCESS DEVELOPMENT AND CHARACTERIZATION OF IMMORTALIZED SALIVARY GLAND EPITHELIAL CELL LINES RFA AVAILABLE: 89-DE-3 P.T. 34; K.W. 0780000, 0780015, 1002058, 0790005 National Institute of Dental Research Application Receipt Date: December 13, 1989 PURPOSE The Caries, Restorative Materials, and Salivary Research Branch of the Extramural Program of the National Institute of Dental Research (NIDR) invites investigator-initiated applications for regular research project grants to develop and characterize immortalized normal human and rodent salivary gland (all types, both major and minor) epithelial (both acinar and ductal) cell lines with appropriate phenotypic expression. Immortalized cell lines resembling their parental strain in essential characteristics would greatly facilitate definitive studies of salivary-specific gene expression in developing and adult glands, molecular mechanisms of salivary gland exocytosis, and regulation of fluid and electrolyte transport. This RFA is for a single competition with a receipt date of December 13, 1989, and may be reissued at a later date. BACKGROUND The importance of saliva in maintaining the health of the hard and soft tissues of the mouth is well established. While great strides have been made in elucidating the mechanisms which regulate the synthesis and secretion of saliva, we know very little about the molecular mechanisms which control these functions. A central issue in eucaryotic molecular biology is to elucidate the mechanisms which regulate the tissue- specific expression of unique sets of genes. Clearly, this is a highly relevant and critical area to be addressed if we are to continue to increase our understanding of how salivary glands work. Transcription of eucaryotic genes by RNA polymerase II is regulated by modular cis-acting DNA sequences (promoters and enhancers) which bind to specific transcription (trans-acting) factors. Some of the cis-acting elements are common to all genes, whereas others are unique to sets of genes whose expression is regulated in a coordinate manner. Related regulatory sequences have been identified within the 5' flanking regions of several genes of the exocrine rat pancreas. It will be very important to establish if similar sequences code for salivary-specific genes. Through understanding the coordinate regulation of salivary-specific gene expression, we may finally gain an appreciation of how salivary molecules work together to exert their maximum protecting effect within the inhospitable oral environment. Trans-acting proteins bind specifically to cis-acting DNA regions and thereby serve to either increase or inhibit transcription. Several of these factors have been identified by DNA footprinting and gel retardation assays, although none have yet been examined in salivary glands. How specific protein-DNA interactions regulate gene expression is not yet clear, but an understanding of these interactions will permit the synthesis of novel gene- specific "regulators." Superimposed over the direct level of control exerted by transacting factors are the numerous hormones which have a profound influence on gene expression. Given that the primary function of salivary glands is to secrete, it is not surprising that intracellular mediators of exocytosis such as cyclic AMP or calcium also influence gene transcription. The extent to which secretion and transcription are coupled remains a critical question. Studies of this type have thus far been performed with acute preparations of cells (i.e., short-term tissue culture procedures), predominantly from the parotid gland. At present, there are no differentiated cell lines available to study salivary acinar cell function. The development of immortalized cell lines capable of maintaining a differentiated acinar cell phenotype would greatly facilitate biochemical and physiological analysis of these cells. In particular, this would permit a direct analysis of salivary acinar cell physiology and function with the techniques of molecular biology. These studies are not readily performed with primary cultures due to the inability to generate sufficient numbers of cells in a reproducible fashion. In particular, study of mucin- producing cells such as minor salivary glands have lagged due to scarcity of tissue. Although epithelial cells have proven extremely difficult to immortalize and/or transform, recent success in this area has suggested that the techniques are now available to undertake this challenge. In general, immortalization and/or transformation of epithelial cells is associated with a reduction or loss of epithelial cell-specific properties. It is critical, therefore, to insure that generated immortalized cell lines continue to resemble their parental strain in essential characteristics. To this end, reliable markers must be developed to allow for rapid and accurate assessment of unique cellular characteristics. Ideal candidates would include cDNA's coding for tissue-specific chain products as well as antibodies to these products. In this fashion both transcriptional levels as well as competence in exocytosis would be evaluated. Recent studies have, in fact, identified suitable candidate markers for mucous and serous acinar cells and for different components of the duct system. Immortalization and transformation of epithelial cells has been accomplished using oncogenic viruses, oncogenes, or through spontaneous cell immortalization. Utility of each of these methods requires exploration for use in salivary acinar cells. An originless SV40 plasmid offers the theoretical advantage of low levels of virus replication, and, thus, should avoid problems with reintegration of the virus and the concomitant loss of differentiated characteristics. It would be desirable to employ temperature-sensitive or heavy metal ion-sensitive mutants of SV40 since immortalization and/or transformation by oncogenes often blocks aspects of differentiation. The use of a temperature- or heavy metal ion-sensitive mutant would permit modulation of the transformed phenotype. Retroviral vectors have also been useful for introducing exogenous DNA into recipient cells. In particular, a retroviral vector containing the adenoviral Ela gene product has been used to immortalize epithelial cells from a broad range of rat tissues. As tissue- and cell- specific genes are characterized, it may be possible to further specify the expression of such oncogenic materials by driving the oncogene constructs with regions of the promoters which specify tissue and/or cellular specificity. Appropriate cell lines will ultimately provide the tools to examine the basic molecular mechanisms which regulate salivary gland development, differentiation, function, and renewal. OBJECTIVES AND SCOPE The Salivary Glands and Secretions Program of this Branch invites regular research project grant applications for support of research on the development and characterization of immortalized salivary gland epithelial cell lines capable of maintaining the differentiated parental strain phenotype. In addition to studies in areas 1 and 2 described below, both of which are obligatory, applicants may include in their research proposals studies related, but not necessarily limited, to one or more of the following areas: 1 Immortalization of differentiated, normal, human and rodent salivary gland epithelial cells of one or more types, including mucous and serous acinar cells and intercalated, striated, granular, and excretory duct cells from both major and minor glands. 2 Characterization of the functional (including transport), structural, and antigenic properties of immortalized cells. 3 Development of techniques for growing cells into confluent monolayers suitable for transepithelial transport studies. 4 Studies of matrices (i.e., collagens, fibronectin, etc.) useful for cell growth and differentiation. 5 Coculture of salivary gland epithelial cells with various mesenchymal cells that may influence growth and differentiation of the former. 6 Hormonal requirements for cell growth and differentiation. 7 Study of factors leading to or inhibiting dedifferentiation of cultured cells. 8 Cloning of specific differentiated subsets of epithelial cells derived from both normal and cancer cell lines. 9 Development of cDNA libraries of cloned cell lines. 10 Development of reliable markers for rapid and accurate assessment of unique salivary gland epithelial cellular characteristics. According to the Public Health Service (PHS) policy relating to distribution of unique research resources produced with PHS funding (NIH Guide for Grants and Contracts, Vol. 17, No. 29, September 16, 1988, pages 1- 2), awardees of these grants would be encouraged to either distribute new long-lasting or immortalized salivary gland epithelial cell lines through their own laboratory or institution or submit them to entities such as the American Type Culture Collection or similar repositories in order to facilitate their availability for research purposes to the scientific community. MECHANISM OF SUPPORT Support for this initiative will be through research project grants (R01). It is anticipated that up to four awards will be made, if a sufficient number of high quality applications is received. Although funds have been allocated for this program in NIDR's plans for fiscal years 1990 through 1994, award of grants resulting from this RFA is contingent upon receipt of appropriated funds for this purpose. Applicants may request up to five years of support. Subsequent support will be contingent upon program needs and grantees' performance, as determined by peer review. Policies that govern research grant programs of the National Institutes of Health will prevail. APPLICATION AND REVIEW PROCEDURES Applications in response to this RFA will be reviewed by a Special Review Committee convened by the NIDR's Scientific Review Branch. Secondary review will be by the National Advisory Dental Research Council tentatively in May 1990. Review criteria include the significance and originality of the research goals and approaches; feasibility of the research and adequacy of the study design; training, experience, and research competence of the investigator(s); adequacy of available facilities; provisions for protection of human subjects and the humane care and use of laboratory animals; and the appropriateness of the requested budget for the work proposed. Funding decisions will be based on Initial Review Group and National Advisory Dental Research Council recommendations, relevance to the objectives and scope of the RFA, and the availability of appropriated funds. The earliest funding date is July 1, 1990. Applications should be submitted on Form PHS-398 (Revised 10/88), available in the business or grants office of most academic or research institutions or from the Division of Research Grants, NIH. Applications received after December 13, 1989, and those which are deemed nonresponsive to the RFA will be assigned to a Division of Research Grants Study Section for initial review and will be considered with other nonsolicited grant applications received during that review cycle. To identify the application as a response to this RFA, check "yes" on Item 2 of the first (face) page of the application and enter "RFA: 89-DE-3: IMMORTALIZED SALIVARY GLAND EPITHELIAL CELL LINES" in the space provided. The RFA label available in the 10/88 revision of Application Form 398 must be affixed to the bottom of the face page. Failure to use this label could result in delayed processing of your application such that it may not reach the review committee in time for review. The original and four copies of the application should be received by December 13, 1989, at: Grant Application Receipt Office Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892-4500** Two exact copies of the application should also be sent by December 13, 1989, to: Dr. H. George Hausch Chief, Scientific Review Branch National Institute of Dental Research Extramural Program Westwood Building, Room 519 Bethesda, MD 20892-4500 Telephone: (301) 496-7658 All inquiries concerning this RFA should be directed to: G. G. Roussos, Ph.D. Chief, Caries, Restorative Materials, and Salivary Research Branch National Institute of Dental Research Westwood Building, Room 505 Bethesda, MD 20892-4500 Telephone: (301) 496-7884 This program is described in the Catalog of Federal Domestic Assistance No. 13.121, Diseases of the Teeth and Supporting Tissues. Awards will be made under authorization of the Public Health Service Act, Title III. Section 301 (Public Law 78-410, as amended; 42 USC 241) and administered under PHS grant policies and Federal Regulations 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. REQUEST FOR RESEARCH GRANT APPLICATIONS (RFA): NIH-89-HL-11-L INTERVENTIONS FOR CONTROL OF ASTHMA AMONG BLACK AND HISPANIC CHILDREN P.T. 34, FC, FD; K.W. 0715013, 0795003 National Heart, Lung, and Blood Institute * Application receipt date: December 1, 1989 PURPOSE The purpose of this solicitation is to encourage demonstration and education research to develop, implement, and evaluate interventions to achieve long-term control of asthma among Black and Hispanic children. DISCIPLINES AND EXPERTISE This research solicitation may be of interest to investigators from a broad range of disciplines such as pulmonary medicine, pediatrics, behavioral sciences, epidemiology, public health, biostatistics, health education, and communication sciences. Multidisciplinary approaches involving several specialties are appropriate to meet the goals of the research. Applicants must demonstrate access to target and comparison populations and expertise within the research team to carry out research sensitive to the sociocultural elements of the minority population. BACKGROUND Asthma is a significant health problem in the United States, affecting approximately 10 million people. Approximately 10 percent of all individuals in the U.S. have asthma or frequent wheezing at some point in their lives. The chronic condition results in high medical care costs and absenteeism from work or school. Although there remains a lack of agreement on a standard medical treatment regimen, it is possible, generally through drug treatment and self management, for most patients to achieve adequate control of asthma symptoms. The problem of asthma among minority populations, especially Blacks, appears to be greater than among whites. Although morbidity and mortality data related to asthma among minority populations are incomplete, there is evidence that asthma is more prevalent among Blacks and those living below the poverty level. Asthma deaths of Blacks have reported to be three times higher than, and hospitalization rates twice those of whites. Control of asthma is dependent upon both adequate medical treatment and effective self-management. Yet minority populations often do not have adequate medical care because of inaccessibility to and under-utilization of health care services. For example, in a program with Latino children and their parents, significant barriers to continuing health care were encountered. Before an asthma education program could be provided, it was first necessary to assure adequacy of medical attention and appropriate drug therapy. Indeed, national data have indicated the disparity between nonminorities and minorities with respect to health and access to medical care. Furthermore, minority populations, especially those at lower socioeconomic levels, may have different medical care patterns, e.g., greater reliance on emergency rooms for routine medical care. Other barriers may also be associated with inadequate control of asthma, especially among minority populations. These may include nonadherence to treatment regimens, lack of effective education programs to assure appropriate self-management, low educational and literacy levels, and language preferences. In addition, communication and cultural differences between health care providers and patients may impede effective provider-patient interactions. Thus, there may be various and numerous barriers to be overcome in order to achieve control of asthma among minorities. This initiative is designed to generate research projects that develop, implement, and evaluate interventions for minority children that will reduce the morbidity from asthma. Over the past decade the Division of Lung Diseases has supported a number of asthma self-management studies. However, only a few of these studies were targeted at populations that were predominately minority, and the findings from those few indicated that special strategies are needed to reach inner city minority populations. The focus of this initiative is the development of programs to control asthma that meet the needs of Black and Hispanic populations. Innovative programs that can serve as model programs in a variety of settings, e.g., hospitals, health maintenance organizations, private practice, outpatient centers, and community settings, are encouraged. OBJECTIVES AND SCOPE Research is needed to determine the most effective methods to manage asthma among minority children. This RFA would provide grant funds for the design, implementation, and evaluation of interventions to improve the control of asthma among Blacks and Hispanics. The goal of this solicitation is the development of model, replicable programs that reduce the morbidity caused by asthma, decrease inappropriate use of health care resources, and enhance the quality of life of asthmatics. Studies should focus on children with asthma from predominately Black and/or Hispanic populations; any age group up to 18 years may be included, as well as parents of the children. The studies, which should be prospective in nature, can be conducted in any of a variety of settings, including hospitals, health maintenance organizations, private medical practices, outpatient clinics, and other community settings. As a component of the overall program, interventions could include those aimed at changing the knowledge and behaviors of health care providers, as well as those of patients and their families and other groups within the community. These studies may also provide information regarding the relationship between source of health care and/or source of payment with patient management and medical outcome. Approaches which mobilize community resources to increase access to care, integrate patient education into medical care, and educate health professionals about asthma and its management are encouraged. Examples of questions that could be answered by programs developed through this solicitation include the following: o How can patients at high risk be targeted for early intervention in order to avoid emergency room visits and hospitalizations for asthma? o How can significant barriers to ongoing medical care and self-management be overcome? o How can patient/family education be effectively integrated into health care systems used by these populations? o How can education of health care providers contribute to improved management of asthma among minority children? o What strategies are needed to assure that patients receive an appropriate treatment regimen? o What are the relationships between interventions and medical outcomes? o What is the effect of intervention on quality of life and family functioning? o What interventions are most effective among Black populations? Among Hispanic populations? Innovative interventions are encouraged involving the patients and their families, use of community resources (e.g., the schools), special approaches (e.g., community asthma control centers), and program strategies based upon the cultural characteristics of the population. Applications from minority scientists and minority institutions are especially encouraged. Research designs should include the following elements: o a specified, well-defined population of Black and/or Hispanic children with asthma o reliable and valid assessment of their asthma and provisions for monitoring changes in the disease o an appropriate theoretical basis for the interventions o sufficient population to provide for a control or comparison group and to permit evaluation of the efficacy of the program o evidence that the cultural and social characteristics of the study population have been taken into account in the study design and implementation of the program o measurements of health status and behavior change in relation to control of asthma (assessments of other factors such as knowledge, compliance, quality of life, use of medical care services, and cost effectiveness are also encouraged.) o ability to obtain follow up data on patients for two years to assess the efficacy of the interventions over time. Though the research design may build from existing asthma control programs, the proposal should test a hypothesis specifically related to the targeted minority population(s) or include innovative approaches to interventions. Funding requests for support of existing asthma control programs without a research component would not be considered responsive to this solicitation. Investigations of the effectiveness of clinical therapies will also be excluded. Interdisciplinary approaches that include medical, behavioral science, and education are strongly encouraged. If collaborative arrangements through subcontracts with other institutions are planned, consult the NHLBI Grants Operations Branch (301) 496-7255 regarding procedures. MECHANISM OF SUPPORT The support mechanism for this program will be the Demonstration and Education Research Program Grant. It is anticipated that a maximum of four grants of up to five years each will be awarded under this one-time solicitation. The specific amount to be funded, however, will depend on the merit and scope of the applications received, their critical relevance to the program objectives, and the availability of funds. Since a variety of approaches would represent valid responses to this announcement, it is anticipated that there will be a range of costs among individual grants awarded. Support of grants pursuant to this RFA is contingent upon availability of funds for this purpose. Upon initiation of the program, the Division of Lung Diseases will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program. In the preparation of the budget for the grant application, applicants should request travel funds for a two-day meeting each year, probably to be held in Bethesda, Maryland. Applicants should also include a statement in their applications indicating their willingness to participate in such meetings and cooperate with other researchers in this program. Applicants are requested to furnish their own estimates of the time required to achieve the objectives of the proposed research project; however, the award period for this activity must not exceed five years. At the end of the initial award period, renewal applications may be submitted for further competitive review through the regular grant program of the NIH. It is anticipated that support will begin in August 1990. The current policies and requirements that govern the research grant programs of the PHS will prevail, including the institutional requirements for safe-guarding the rights and welfare of human subjects who participate in the proposed studies. REVIEW PROCEDURES AND CRITERIA Review Method. All applications responding to this RFA will be reviewed for scientific and technical merit by an initial review group, which will be convened by the Division of Extramural Affairs, NHLBI, to review these applications. Upon receipt, applications will be reviewed for their responsiveness to the objectives of this RFA. If an application is judged unresponsive at this stage, the applicant will be contacted and given an opportunity to withdraw the application or to have it considered for the regular research grant program of the NIH. If the proposal submitted in response to this RFA is substantially similar to a research grant application already submitted to the NIH for review, the applicant will be asked to withdraw either the pending application or the new one. Simultaneous submission of identical applications will not be allowed. Review Criteria. The factors to be considered in the evaluation of scientific merit of each application will be similar to those used in the review of traditional research- project grant applications, including the following: o the quality of the science o the originality and feasibility of the approach o the training, experience, and research competence of the investigator(s) o the adequacy of the experimental design o the suitability of the facilities o the appropriateness of the requested budget to the work proposed o the importance of the proposed research to the objectives of the RFA METHOD OF APPLYING Letter of Intent Prospective applicants are asked to submit a one-page letter of intent that includes a descriptive title of the project and an identification of any other participating institutions or investigators. The Institute requests such letters only for the purpose of providing an indication of the number and scope of applications to be received and therefore usually does not acknowledge their receipt. A letter of intent is not binding and is not a requirement for application. This letter of intent, which should be received no later than November 1, 1989, should be sent to: James Scheirer, Ph.D. Division of Extramural Affairs, NHLBI National Institutes of Health Westwood Building, Room 648 Bethesda, Maryland 20892 Format for Applications Submit applications on form PHS 398 (rev. 10/88), the application form for the traditional research-project grant. This form is available in an applicant institution's office of sponsored research or business office. Use the conventional format for research-project grant applications and ensure that the points identified in the section on "Review Procedures and Criteria" are fulfilled. To identify the application as a response to this RFA, check "yes" on Item 2 of page 1 of the application and enter the title "Control of Asthma Among Black and Hispanic Children" and RFA number NIH-89-HL-11-L. Application Procedure Send or deliver the completed application and four (4) signed, exact photocopies to: Division of Research Grants Westwood Building, Room 240 National Institutes of Health Bethesda, Maryland 20892** Send an additional two (2) copies of the application to the Chief, Review Branch at the address listed under Letter of Intent. Applications must be received by December 1, 1989. An application not received by this date will be considered ineligible. Timetable Letter of intent November 1, 1989 Application receipt date December 1, 1989 Initial Review February 1990 Review by the National Heart, Lung, and Blood Advisory Council May 24-25, 1990 Anticipated award date August 1990 Inquiries Inquiries regarding this announcement may be directed to the program administrator: Joan M. Wolle, Ph.D., M.P.H. Prevention, Education, and Research Training Branch Division of Lung Diseases, NHLBI Westwood Building, Room 640 Bethesda, MD 20892 (301) 496-7668 * The programs of the Division of Lung Diseases, National Heart, Lung, and Blood Institute, are identified in the Catalog of Federal Domestic Assistance, number 13.838. Awards will be made under the authority of the Public Health Service Act, Section 301 (42 USC 241) and administered under PHS grant policies and Federal Regulations, most specifically 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental Review Requirements of Executive Order 12372, or to review by Health Systems Agency.