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From: Dot Baker <UNCDOT@UNC.BITNET>
Subject: June l5, l990 NIH Guide
To: pjones@UNCVX1.BITNET

Good Afternoon Paul,
    This is one of two articles coming to you today for the NIH Guide
Listserver.  Please post this one as: NIHGUIDE.061590.
    Thanks,  Have a nice afternoon.
                                   Dottie
 ---------------------------- Text of forwarded message -----------------------
     
NIH GUIDE - Vol. 19, No. 22, June 15, 1990
     
     
                                   NOTICES
     
     
NOTICE OF MEETING - ELECTRONIC AVAILABILITY OF THE NIH GUIDE FOR GRANTS
AND CONTRACTS ...........................................(84/106)............ 1
National Institutes of Health
Index:  NATIONAL INSTITUTES OF HEALTH
     
     
                   NOTICES OF AVAILABILITY (RFPs AND RFAs)
     
     
OPERATIONS OFFICE (RFP) .................................(112/182)........... 1
National Institute of Allergy and Infectious Diseases
Index:  ALLERGY, INFECTIOUS DISEASES
     
     
ASTHMA AND ALLERGIC DISEASE COOPERATIVE RESEARCH CENTERS
(RFA AI-90-05) ..................................(185/313, 804/1584)......... 2
National Institute of Allergy and Infectious Diseases
Index:  ALLERGY, INFECTIOUS DISEASES
     
     
IMMUNOLOGIC DISEASE COOPERATIVE RESEARCH CENTERS (RFA AI-90-06) ..(321/454).. 4
National Institute of Allergy and Infectious Diseases      (1587/2261)
Index:  ALLERGY, INFECTIOUS DISEASES
     
     
                        ONGOING PROGRAM ANNOUNCEMENTS
     
     
BIOLOGY OF AGING SKIN (PA-90-16) ..........................(460/773)......... 5
National Institute on Aging
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Index:  AGING, ARTHRITIS, MUSCULOSKELETAL DISEASES, SKIN DISEASES
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
                                   NOTICES
     
     
NOTICE OF MEETING - ELECTRONIC AVAILABILITY OF THE NIH GUIDE FOR GRANTS AND
CONTRACTS
     
P.T. 16; K.W. 1004017
     
National Institutes of Health
     
A meeting will be held on September 7, 1990, in Bethesda, Maryland, area
concerning the electronic transmission of the NIH Guide for Grants and
Contracts.  In response to the notice published in the NIH Guide for Grants
and Contracts on April 20 (Vol. 19, No. 16), a number of people have
expressed interest in a conference concerning the electronic Guide.
     
As plans are finalized, information and details will be announced in the
Guide.  Please feel free to contact:
     
Ms. Rebecca Duvall
Institutional Liaison Office
National Institutes of Health
Building 31, Room 5B31
Bethesda, MD  20892
Telephone:  (301) 496-5366
BITNET:  Q2C@NIHCU
     
     
                   NOTICES OF AVAILABILITY (RFPs AND RFAs)
     
     
OPERATIONS OFFICE
     
RFP AVAILABLE:  RFP-NIH-NIAID-DAIDS-91-07
     
P.T. 34; K.W. 0755015, 0755018
     
National Institute of Allergy and Infectious Diseases
     
The National Institute of Allergy and Infectious Diseases (NIAID), National
Institutes of Health, is soliciting proposals from small business
organizations having the capabilities and facilities to provide the Division
of Acquired Immunodeficiency Syndrome Treatment Research Program with
scientific, technical, and operational support to facilitate and significantly
reduce the time required to develop, implement, and bring clinical trial
protocols to successful conclusion.
     
This critical contract support will be provided within a research environment
and consortium of organizations called the AIDS Clinical Trials Group (ACTG).
The ACTG brings together the AIDS Clinical Trials Unit clinical investigators
and their institutions, the ACTG Statistical Data and Analysis Center, the
Food and Drug Administration, the pharmaceutical industry, HIV-infected
patients and their advocates, and Treatment Research Program scientific and
administrative personnel to make key decisions about AIDS treatment research
issues and conduct clinical trials.
     
Specifically, the selected Contractor must have the demonstrated scientific,
technical, and operational capabilities necessary to play a critical role in
the development and review/evaluation of proposed clinical trials protocols;
the implementation and conduct of protocols; and the successful completion of
protocols.  Experience and expertise in the protocol development process,
including scientific literature searches and evaluation of methodologies; the
ability to monitor the progress of studies and to identify problems and
recommend corrective actions and the ability to relate effectively with
clinical trials investigators, pharmaceutical industry sponsors, and
statistical contractors are all prerequisites for competing under this Request
for Proposal (RFP).  The nature and complexity of the work under this RFP has
evolved substantially in scope and complexity since the establishment of the
ACTG in December l987.  This is due in part to the sheer numbers of proposed
and implemented protocols, field monitoring and data management tasks,
regulatory issues, accountability to multiple organizations, and information
flow requirements.
     
This NIAID-sponsored project will be for five years.  A cost-plus-fixed-fee
contract is anticipated.
     
     
     
     
             NIH GUIDE - Vol. 19, No. 22, June 15, 1990 - Page 1
This is an announcement for an anticipated RFP.  RFP-NIH-NIAID-DAIDS-9l-07
shall be issued on or about June l5, l990, with a closing date tentatively set
for August l5, l990.
     
Requests for the proposal should be directed in writing to:
     
Nancy M. Hershey
Contract Management Branch
National Institutes of Allergy and Infectious Diseases
National Institutes of Health
Control Data Corporation Bldg., Room 222P
6003 Executive Boulevard
Bethesda, MD  20892
Telephone:  (301) 496-0193
     
To receive a copy of the RFP, please provide this office with two (2)
self-addressed mailing labels.  (THIS IS A l00% SET-ASIDE FOR SMALL BUSINESS).
All responsible small business sources may submit a proposal which shall be
considered by NIAID.  One award is anticipated.  This acquisition applies to a
7379 size standard for computer related services, NEC.
     
This advertisement does not commit the Government to award a contract.
     
     
ASTHMA AND ALLERGIC DISEASE COOPERATIVE RESEARCH CENTERS
     
RFA AVAILABLE:  AI-90-05
     
P.T. 04; K.W. 0715013, 0710070, 0715110, 0715026, 0785035, 0710030
     
National Institute of Allergy and Infectious Diseases
     
Letter of Intent Receipt Date:  July 27, 1990
Application Receipt Date:  October 24, 1990
     
BACKGROUND INFORMATION
     
The Asthma and Allergy Branch of the Division of Allergy, Immunology and
Transplantation (DAIT) of the National Institute of Allergy and Infectious
Diseases (NIAID) sponsors fundamental and clinical research concerned with
asthma, allergic and immunologic diseases and with relevant mechanisms of
hypersensitivity and inflammation.  For this purpose, twelve Asthma and
Allergic Disease Centers (AADC) are currently funded.  Participation of DAIT
staff would be a valuable resource in order to improve the ability of the
awardees to design and implement the dissemination of information or
technology transfer in the Demonstration and Education projects by
coordinating multi-Center projects and would provide cooperative support in
planning and data analysis (where needed).  It would also improve
communication and networking between awardees, foster sharing of information
and reagents, and prevent duplication of effort.  In order to achieve these
objectives, the NIAID intends to phase in a network of Asthma and Allergic
Disease Cooperative Research Centers (AADCRC) and phase out the AADC.  The
present request for applications (RFA) is designed to encourage and invite the
development of proposals from interdisciplinary clinical investigative groups
interested in integrated studies of asthmatic and allergic processes.  New
applicants, as well as holders of an AADC grant whose support is terminating,
may submit applications for an AADCRC cooperative agreement.  Other current
holders of an AADC grant may not apply.
     
RESEARCH GOALS AND SCOPE
     
The fundamental objective of the NIAID's AADCRC program is to foster
acceleration of the application of knowledge of the immune system emerging
from relevant biomedical sciences to clinical hypersensitivity disorders.  The
scope of the AADCRC program involves research designed to foster collaborative
approaches that will integrate basic concepts in allergy, immunology,
pathophysiology, genetics, microbiology, biochemistry, biostatistics,
bioinstrumentation, computer science and pharmacology into clinical
investigations, which, in addition to the fields of allergy and clinical
immunology, may include such areas as dermatology, rheumatology, infectious
diseases, pulmonary medicine, hematology and otorhinolaryngology, when a high
degree of relevance to immunology exists.  Because the role of
hypersensitivity and immune-related inflammatory mechanisms has become
increasingly evident in disorders of the skin, immunodermatologic studies are
especially encouraged within an AADCRC.
     
Since transfer of the results of basic and clinical science to the community
is an important objective of the AADCRC, a required feature of the AADCRC will
     
             NIH GUIDE - Vol. 19, No. 22, June 15, 1990 - Page 2
be at least one Demonstration and Education research project, which will test
the effectiveness of interventions to promote health or prevent disease in
defined populations.  Because of the alarming increase in asthma mortality and
morbidity since 1979 in minority populations in urban environments, this
research will focus on asthma in minority residents in the inner city.
Education and demonstration research in this area will be developed as a
consensus process in a Coordinating Committee.  Demonstration and education
research is the testing of the effectiveness of interventions to promote
health or prevent disease in defined populations.  The interventions selected
for such testing should be those that have already been found to be
efficacious in other studies and include, but are not limited to, education
strategies and modifications in health care and health-related practices.  The
studies should be based on fields of biomedical, behavioral, and social
sciences.
     
The NIH places special emphasis on the need for inclusion of minorities and
women in studies of diseases which disproportionately affect them and also
urges that applicants/offerors give added attention, where feasible and
appropriate, to their inclusion in other clinical studies.  For proposed
population-based studies, access to and inclusion of appropriate minority
urban populations will be a necessity in order to perform the requisite
clinical research.
     
MECHANISMS OF SUPPORT
     
Award(s) will be made as a Cooperative Agreement.  This is an assistance
relationship with substantial involvement of NIAID staff.  An AADCRC
Cooperative Agreement is awarded to an institution on behalf of a program
director for support of a broadly based, multi-disciplinary long-term research
program which has a specific objective or basic theme of research on asthma or
allergic diseases.  An AADCRC generally will involve the organized efforts of
groups of investigators who conduct research projects related to the overall
program objective.  The agreement can provide support for the projects and for
certain basic resources shared by individuals where the sharing facilitates
the total research effort.  Overall, each component project should demonstrate
an essential element of unity and interdependence.  In FY 1991 the NIAID plans
to award at least two AADCRC cooperative agreements and depending on
availability of funds and scientific merit more than two.  Budgetary requests
should be limited to no more than $500,000 total direct costs.
     
METHOD OF APPLYING
     
Before preparing an application, the prospective applicant should request a
copy of the NIAID Information Brochure on Program Projects, Centers and
Cooperative Agreements from:
     
Dr. Kamal Mittal
Executive Secretary
Allergy, Immunology and Transplantation Research Committee
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Westwood Building, Room 3A06
Bethesda, MD  20892
Telephone:  (301) 496-3528
     
STAFF CONTACT
     
The complete RFA may be obtained from:
     
Lawrence J. Prograis, Jr., M.D.
Chief, Asthma and Allergy Branch
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Westwood Building, Room 752
National Institutes of Health
Bethesda, MD  20892
Telephone:  (301) 496-8973
Telefax:  (301) 402-0175
     
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.
     
     
     
     
     
     
             NIH GUIDE - Vol. 19, No. 22, June 15, 1990 - Page 3
IMMUNOLOGIC DISEASE COOPERATIVE RESEARCH CENTERS
     
RFA AVAILABLE:  AI-90-06
     
P.T. 04; K.W. 0710070, 0755018, 0715013, 0403004, 0404000, 0755030, 0765033
     
National Institute of Allergy and Infectious diseases
     
Letter of Intent Receipt Date:  July 27, 1990
Application Receipt Date:  October 24, 1990
     
BACKGROUND INFORMATION
     
The Clinical Immunology Branch of the Division of Allergy, Immunology and
Transplantation (DAIT) of the National Institute of Allergy and Infectious
Diseases (NIAID) supports research on cellular and molecular mechanisms of
immunologic diseases and the application of this knowledge to clinical
problems.  To support these objectives, 6 Centers for Interdisciplinary
Research in Immunologic Diseases (CIRID) are currently funded.  The NIAID
intends to phase in a network of Immunologic Disease Cooperative Research
Centers (IDCRCs) and phase out the CIRIDs for the purpose of having
programmatic involvement by DAIT staff in order to improve the ability of the
awardees to design and implement the dissemination of information or
technology transfer in the Demonstration and Education projects by
coordinating multi-Center projects and would provide cooperative support in
planning and data analysis (where needed).  It would also improve
communication and networking between awardees, foster sharing of information
and reagents, and prevent duplication of effort.  This request for
applications (RFA) is intended to encourage the development of applications
from collaborative basic science and clinical investigative groups concerned
with the study of immunologic diseases.  New applicants, as well as holders of
a CIRID grant whose support is terminating, may submit applications for an
IDCRC cooperative agreement.  Other current holders of a CIRID grant may not
apply.
     
RESEARCH GOALS AND SCOPE
     
The fundamental objective of the IDCRC program is to foster acceleration of
the application of knowledge of the immune system generated by research in the
relevant biomedical sciences to clinical investigations concerned with
immunologic disorders, including asthma and allergic diseases.  The goals of
the IDCRCs are increased knowledge of the etiology and pathogenetic mechanisms
of immunologic diseases and improvements in diagnosis, treatment and
prevention of these disorders.
     
The scope of the IDCRCs includes basic and clinical studies of primary
immunologic diseases and other diseases in which a role for the immune system
can be identified.  Some research areas of interest are inherited and acquired
immunodeficiency diseases, autoimmune disorders, interactions of the immune
and endocrine systems (e.g. type 1 diabetes), interactions of the immune and
nervous systems (e.g. multiple sclerosis), acute and chronic inflammation,
immunopathologic aspects of host defense and phagocytes, leukocyte and
complement system dysfunctions, asthma and other allergic diseases, and drug
reactions.  Study of a spectrum of allergic diseases, including asthma should
be recognized as one necessary component of a Cooperative Center's program in
immunologic diseases.
     
The transfer of the results of basic and clinical science to the community is
an important objective of the IDCRC.  Therefore, a required feature of the
IDCRC program is the inclusion of at least one Demonstration and Education
Research Project.  Due to the alarming increase in asthma mortality and
morbidity since 1979, especially in urban environments, this research will
focus on asthma in minority residents in the inner city.  Demonstration and
education research in this area will be developed as a consensus process in a
Coordinating Committee.  Demonstration and education research is the testing
of the effectiveness of interventions to promote health or prevent disease in
defined populations.  The interventions selected for such testing should be
those that have already been found to be efficacious in other studies and
include, but are not limited to, education strategies and modifications in
health care and health-related practices.  The studies should be based on
fields of biomedical, behavioral, and social sciences.
     
The NIH places special emphasis on the need for inclusion of minorities and
women in studies of diseases which disproportionately affect them and also
urges that applicants/offerors give added attention, where feasible and
appropriate, to their inclusion in other clinical studies.  For proposed
population-based studies, access to and inclusion of appropriate minority
     
     
             NIH GUIDE - Vol. 19, No. 22, June 15, 1990 - Page 4
urban populations will be a necessity in order to perform the requisite
clinical research.
     
MECHANISM OF SUPPORT
     
Award(s) will be made as a Cooperative Agreement.  This is an assistance
relationship with substantial involvement of NIAID staff.  An IDCRC
Cooperative Agreement is awarded to an institution on behalf of a program
director for support of a broadly based, multidisciplinary or
interdisciplinary, long-term research program which has a specific major
objective or basic theme.  An IDCRC generally involves the organized efforts
of groups of investigators, members of which conduct research projects related
to the overall program objective.  The agreement can provide support for the
projects and for certain core resources shared by individuals in a program
where the sharing facilitates the total research effort.  Overall, the
projects should demonstrate an essential element of unity and interdependence.
     
In FY 1991, the NIAID plans to award at least one IDCRC cooperative agreement
and depending on availability of funds and scientific merit more than one.
budgetary requests should be limited to no more than $500,000 total direct
costs.
     
METHOD OF APPLYING
     
Before preparing an application, the prospective applicant should request a
copy of the NIAID Information Brochure on Program Projects, Centers and
Cooperative Agreements from:
     
Dr. Kamal Mittal
Executive Secretary
Allergy, Immunology and Transplantation Research Committee
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Westwood Building, Room 3A06
Bethesda, MD   20892
Telephone:  (301) 496-3528
     
STAFF CONTACT
     
A more detailed RFA may be obtained from:
     
Howard B. Dickler, M.D.
Chief, Clinical Immunology Branch
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Westwood Building, Room 755
Bethesda, MD  20892
Telephone:  (301) 496-7104
Telefax:  (301) 480-3780
     
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.
     
     
                        ONGOING PROGRAM ANNOUNCEMENTS
     
     
BIOLOGY OF AGING SKIN
     
PA:  PA-90-16
     
P.T. 34; K.W. 0710010, 0715185, 1002004, 0760020, 0755030
     
National Institute on Aging
National Institute of Arthritis and Musculoskeletal and Skin Diseases
     
INTRODUCTION
     
Intrinsic Aging.  Skin provides an excellent model to study the fundamental
molecular mechanisms of intrinsic biological aging.  Several physiological,
structural and biochemical changes occur in aging human skin.  Cutaneous cell
replacement, structural integrity of the epidermis and dermis, immune
response, wound repair, and vascular responsiveness are compromised in aged
skin.  Skin is a highly accessible organ where biopsy specimens can provide
tissue and/or cells for in vivo and in vitro studies.  In addition,
longitudinal data on intrinsic aging changes can be readily obtained.  The
     
             NIH GUIDE - Vol. 19, No. 22, June 15, 1990 - Page 5
three distinct skin compartments, epidermis, dermis, and subcutis, contain a
variety of differentiated cell types.  Well defined, age-dependent changes
have been documented in each of the three compartments.
     
Epidermal keratinocytes produce the stratum corneum which serves as the major
chemical and mechanical barrier of the body.  Keratinocyte turnover rate and
transit from basal compartment to epidermal surface in aged epidermis is
significantly depressed compared to that in young adult tissue.  Flattening of
the dermo-epidermal junction with effacement of epidermal rete pegs and dermal
papillae is a consistent age-dependent change.  Epidermal melanocytes (neural
crest origin) synthesize protective melanin pigment granules.  An
age-dependent decrease in enzymatically active melanocytes is characteristic
in human skin.  Bone marrow-derived Langerhans cells function in antigen
presentation and processing.  The marked reduction in these cells as a
function of age may account, in part, for the age-associated loss of cutaneous
immune responsiveness.
     
The dermis is a complex matrix composed of fibrous proteins and
glycosaminoglycans synthesized by dermal fibroblasts.  The dermis of aged
human skin is relatively acellular and avascular compared to young adult
dermis, having fewer fibroblasts, endothelial cells and mast cells.  Signs of
matrix atrophy are also evident as dermal thinning and structural
deterioration.  Age-dependent changes in elastic fibers, ranging from small
cysts and lacunae to disorganization and fragmentation, are well documented.
Age-dependent changes in collagen are also notable.  The vasculature embedded
in the dermal matrix regulates core body temperature via vasoconstriction and
vasodilation.  Loss of the microvasculature, especially the vertical capillary
loops present in the dermal papillae of young adult skin, is a characteristic
age-dependent change.
     
The subcutis (subcutaneous fat), which provides insulation and mechanical
support, is populated by adipocytes.  Regional loss of subcutaneous fat is
characteristic of aged skin.
     
Photoaging.  Photoaging denotes the degenerative cutaneous changes (actinic
damage) that result from chronic ultraviolet radiation (UVR).  Photoaged skin
is characterized by a telangietactic, leathery, dry surface with blotchy
discolorations, deep wrinkles, accentuated furrows, sags, and bags.  A variety
of benign, premalignant, and malignant lesions are also apparent in photoaged
skin.  Both UVA (320-400 nm) and UVB (290-320 nm) contribute to photoaging of
skin.  UVB is responsible for UV-induced sunburn and is the causative agent
for premalignant actinic keratosis, squamous cell carcinoma, basal cell
carcinoma, and probably malignant melanoma.  UVA (either from sunlight or
artificial tanning light sources) which is capable of deeper skin penetration
than UVB, makes a significant contribution to the characteristic dermal damage
in photoaged skin.
     
Although the photoaging process is often described as "premature aging" or
accelerated normal aging, skin changes due to intrinsic aging and photoaging
are in fact quite distinct and most likely develop via distinct mechanisms.
Marked morphological and structural changes in the epidermis and dermis
underlie the observed deterioration in photoaged skin.  UVR-induced changes in
the epidermis include epidermal thickening, hyperkeratosis, parakeratosis, and
acanthosis.  UVR-damaged basal keratinocytes show altered morphology and
daughter cells show evidence of a defective terminal differentiation program,
with consequent development of irregular (scaly) stratum corneum and multiple
actinic keratoses.  Suprabasal keratinocytes have nuclear inclusions and
excessive melanosome accumulation above the nucleus.  Dyskeratotic
keratinocytes (sunburn cells) also appear in the superficial layers of the
epidermis.  Melanocytes are increased in number, enlarged and found at higher
levels in actinically damaged epidermis.  Chronic UVR also induces freckles
(melanocyte hyperplasia and depletion of injured cells), solar lentigenes
(increased number of highly pigmented melanocytes), and lentigo maligna, a
well established precursor to invasive malignant melanoma.  UVB alters the
immunologic function of Langerhans cells by reduction of antigen-presenting
capability, interruption of the normal effector pathway, and activation of the
T cell suppressor networks leading to an inappropriate immune response.
     
Chronic UVR causes unique dermal deterioration including altered cellular
function, dermal matrix architecture and composition, and vascular structure
and function.  Hyperactive fibroblasts, increased deposition of
glycosaminoglycans, elevated type III:I collagen ratios, and increased amounts
of elastotic material (solar elastosis) are evident in repair zones of
photoaged skin.  Dermal vessels become dilated and leaky, and show excessive
accumulation of basement membrane-like material.  Partially degranulated mast
cells (chronic inflammation) accumulate around damaged vessels.
     
     
     
             NIH GUIDE - Vol. 19, No. 22, June 15, 1990 - Page 6
A significant reduction in photoaging can be achieved with the use of chemical
and physical sunscreening agents and/or limited exposure to sunlight and
artificial UV light sources.  Combination UVA/UVB sunscreens are most
effective for prevention of both epidermal and dermal damage.  New damage to
photoaged skin can be prevented with sunscreening agents and limited exposure
to UVR.
     
SPECIFIC OBJECTIVES
     
The age-dependent biochemical and structural changes in normal, sun-protected
skin are very distinct from those in photoaged skin.  These differences
suggest that intrinsic aging and photoaging are governed by distinct
mechanisms.  The molecular mechanisms which underlie intrinsic aging and
photoaging are not known.  The National Institute on Aging (NIA) wishes to
stimulate research to define the molecular basis of intrinsic aging in skin
and to establish the effectiveness and mode of action of intervention
strategies to retard and/or reverse age-dependent changes.  It is anticipated
that research in this area will yield important information on both
tissue-specific and fundamental regulatory mechanisms involved in biological
aging.  The National Institute of Arthritis and Musculoskeletal and Skin
Diseases (NIAMS) wishes to encourage research to define the molecular
mechanisms which underlie skin photoaging and to establish the effectiveness
and mode of action of agents which may stimulate repair of actinic damage.
     
Molecular Mechanisms of Intrinsic Skin Aging
     
Changes in epidermal and dermal cellularity are well documented age-dependent
changes in sun-protected human skin.
     
  o  Are age-dependent changes in the control of cell proliferation
     involved in cellular loss?
  o  Are changes in the expression of cellular proto-oncogenes, tumor
     suppressor genes or other cell-cycle regulatory molecules
     responsible for the observed age-dependent changes?
  o  Are senescence factors produced by aged skin cells, and if so, by
     what mechanisms do these senescence factors regulate cell
     proliferation and/or terminal differentiation of skin cells?
  o  Are the concentrations of endogenous growth factors altered
     (stimulatory and inhibitory) in aged skin?
  o  Are growth factor signal transduction pathways and cellular
     responses altered in aged skin cells?
     
What are the underlying molecular mechanisms responsible for loss of epidermal
rete pegs and dermal papillae leading to reduced dermo-epidermal adhesion?
     
Disorganization and degeneration of the dermal matrix, including
disorganization of collagen fibrillar units, degradation of elastic fibers,
and loss of matrix glycosaminoglycans is an important component of intrinsic
aging in human skin.
     
  o  Are age-dependent changes in dermal fibroblast gene expression
     involved in dermal matrix degeneration?
  o  Are the observed structural changes related to altered expression
     of collagen I `1 and `2 genes, collagenase, elastin, elastase
     (serine and metalloprotease forms), and stromelysin genes?
  o  Are age-dependent changes in the expression of tissue-specific
     transcription factor genes involved in intrinsic dermal aging?
     
Disorganization and loss of the microvasculature are characteristic changes in
aged skin.
     
  o  Do age-dependent changes in angiogenesis contribute to the observed
     loss?
  o  Are age-dependent changes in endothelial cell gene expression
     contributing factors?
     
Retinoic acid is an endogenous regulator of epidermal keratinocyte and dermal
fibroblast gene expression.
     
  o  Are age-dependent changes in keratinocyte and fibroblast gene
     expression modulated by retinoids?
  o  Are intrinsic age-related changes in epidermis and/or dermis
     reversed by exogenous retinoids (topical retinoid treatment)?
  o  Are age-dependent changes in skin retinoid homeostasis (endogenous
     retinoid metabolite levels and retinoid metabolism) a factor in the
     intrinsic aging of skin?
  o  Are age-dependent changes in retinoic acid receptor gene expression
     (RAR, RARa, RARb) related to intrinsic skin aging?
     
             NIH GUIDE - Vol. 19, No. 22, June 15, 1990 - Page 7
Molecular Mechanisms of Skin Photoaging
     
Actinic damage induces keratinocyte, melanocyte, and dermal fibroblast
hypertrophy in human skin.
     
  o  What are the molecular mechanisms involved in the UVR-induced
     changes in cell proliferation?
  o  Do these cellular alterations arise from acute or long-term changes
     in the control of cell proliferation?
     
Functionally altered fibroblasts appear to be responsible for dermal matrix
degeneration in photoaged skin.
     
  o  What is the molecular basis of chronic UVR-induced solar elastosis?
  o  By what mechanisms does chronic UVR alter collagen I, collagen III,
     and elastin gene expression in the dermal fibroblast?
  o  Does chronic UVR alter collagenase and elastase gene expression,
     and if so, by what mechanisms?
  o  By what mechanisms does chronic UVR affect glycosaminoglycan
     metabolism and deposition in the dermal matrix?
     
Dermal vessels display unique damage and deterioration in photoaged skin.
     
  o  What are the mechanisms whereby chronic UVR alters endothelial cell
     metabolism and function?
  o  What role do mast cells play in vessel damage?  What are the
     underlying mechanisms of mast cell-mediated damage?
     
Chronic UVB exposure has a pronounced and prolonged systemic immunosuppressive
effect due to altered Langerhans cell function and activation of suppressor T
cells.
     
  o  What are the mechanisms responsible for the UVB-induced decreases
     in Langerhans cells in photoaged skin?
  o  What mechanisms are responsible for compromised Langerhans cell
     antigen presentation and processing in photoaged skin?
  o  Which skin cells are involved in the activation of suppressor T
     cells, and what are the molecular mechanisms reponsible for this
     inappropriate immune response?
     
Topical retinoids may enhance the repair of UVR-induced epidermal and dermal
matrix damage in photoaged skin.
     
What are the cellular, biochemical, and structural changes induced by topical
retinoids in photoaged skin?
     
  o  What are the effects of retinoids on gene expression in
     differentiated skin cells (i.e. keratinocytes, fibroblasts,
     endothelial cells)?
  o  What are the molecular mechanisms by which retinoids regulate gene
     expression in skin cells?
  o  Is retinoid homeostasis (levels of endogenous retinoid metabolites,
     expression of retinoid receptors) altered in photoaged skin?
     
APPLICATION AND REVIEW PROCEDURES
     
The primary mechanisms for NIA and NIAMS support of the Biology of Aging Skin
program are:
     
o  Research Project Grant (RO1)
o  Program Project Grant (PO1)
o First Independent Research Support and Transition Award (R29)
o  Fellowship Grants (F32, F33)
     
Applicants should use grant application form PHS 398 (revised 10/88) for RO1,
PO1, and R29 applications and form PHS 416-1 (revised 7/88) for F32 and F33
fellowship applications.  These forms are available at the applicant's
institution or from:
     
Office of Grant Inquiries
Division of Research Grants
Westwood Building, Room 449
National Institutes of Health
Bethesda, MD  20205
Telephone:  (301) 496-7441
     
     
     
     
             NIH GUIDE - Vol. 19, No. 22, June 15, 1990 - Page 8
To expedite the routing of proposals within NIH, please check "yes" in item 2
of the application face page and indicate that the proposal is in response to
NIA/NIAMS:  Biology of Aging Skin PA-90-16.
     
The completed application plus 6 copies should be sent to:
     
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**
     
Receipt dates for Research Project Grant (RO1), Program Project Grant (PO1),
and FIRST Award (R29) applications are February 1, June 1 and October 1;
Fellowship application receipt dates are January 10, May 10, and September 10.
     
All applications submitted in response to this announcement will be assigned
according to standard referral guidelines to appropriate NIH study sections
for initial scientific review and to the appropriate Institute of NIH for
final review by its National Advisory Council or Board.  It is anticipated
that most applications will have dual Institute assignments.  There are no
set-aside funds for these proposals.  Applications will compete for available
funds based on scientific merit.  Traditional NIH review criteria for
scientific and technical merit will apply to all proposals submitted.
     
Applications from women and minority scientists are encouraged.  Inclusion of
minority groups and/or women in study populations, where feasible and
appropriate, is also encouraged by the NIH.
     
Investigators who may be considering submitting proposals in response to the
"Biology of Aging Skin" program announcement are encouraged to discuss their
research goals and the range of grant mechanisms available with NIA or NIAMS
program directors prior to formal submission of research proposals.  The
appropriate Institute Program Directors are:
     
Basic Mechanisms of Intrinsic Aging in Skin
     
Anna M. McCormick, Ph.D.
Director, Genetics Program
Molecular and Cell Biology Branch
Biomedical Research and Clinical Medicine Program
National Institute on Aging
Building 31, Room 5C21
Bethesda, MD  20892
Telephone:  (301) 496-6402
     
Basic Mechanisms of Skin Photoaging
     
Alan N. Moshell, M.D.
Director, Skin Diseases Branch
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Westwood Building, Room 407A
Bethesda, MD  20205
Telephone:  (301) 496-7326
     
     
**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
     
     
     
     
     
     
     
     
     
     
     
     
     
     
     
             NIH GUIDE - Vol. 19, No. 22, June 15, 1990 - Page 9
