Full Text AR-94-001

FAILURE TO HEAL:  CHRONIC WOUND HEALING IN THE SKIN

NIH GUIDE, Volume 22, Number 29, August 13, 1993

RFA:  AR-94-001

P.T.


Keywords: 


National Institute of Arthritis and Musculoskeletal and Skin Diseases
National Institute on Aging
National Institute of Child Health and Human Development
National Institute of Diabetes and Digestive and Kidney Diseases
National Institute of Nursing Research

Letter of Intent Receipt Date:  October 15, 1993
Application Receipt Date:  November 30, 1993

PURPOSE

The National Institute of Arthritis and Musculoskeletal and Skin
Diseases (NIAMS), National Institute on Aging (NIA), National
Institute of Child Health and Human Development (NICHD), National
Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), and
National Institute of Nursing Research (NINR) invite applications for
research on wounds that fail to heal, the prototypic ones being
decubitus (pressure) ulcers, venous (stasis) ulcers and diabetic
ulcers.  Studies may be both basic and applied.  The intent is to
apply knowledge rapidly to the prevention and treatment of chronic
wounds in a clinical/rehabilitation situation.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Failure to Heal:  Pathogenesis of Chronic
Wound Healing in the Skin, is related to the priority area of chronic
disabling conditions.  Potential applicants may obtain a copy of
"Healthy People 2000" (Summary Report:  Stock No. 017-001-00474-0 or
"Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Applications from minority individuals and women are encouraged.
Foreign institutions are not eligible for the First Independent
Research Support and Transition (FIRST) (R29) award.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research grant (R01) and FIRST award (R29) and the newly described
interactive R01 mechanism.  Responsibility for the planning,
direction, and execution of the proposed project will be solely that
of the applicant.  The total project period for applications
submitted in response to the present RFA may not exceed five years.
The anticipated award date is July 1, 1994.  Because the nature and
scope of the research proposed in response to this RFA may vary, it
is anticipated that the size of an award will also vary.  This RFA is
a one time solicitation.  Future unsolicitated competing continuation
applications will compete with all investigator initiated
applications and be reviewed according to the customary peer review
procedures.

FUNDS AVAILABLE

The estimated funds (total costs) available for the first year of
support for the entire program is anticipated to be 1.6 million
dollars.  The anticipated number of new awards is eight.

RESEARCH OBJECTIVES

Background

In spite of recent advances in the basic mechanisms of wound healing,
knowledge of factors involved in the development and treatment of
chronic wounds and their prevention remains limited.  Future progress
in the treatment of chronic wounds will require greater understanding
of their pathogenesis and failure to heal.  These two inseparable
aspects, pathogenesis and failure to heal, were the subject of a
Workshop sponsored by the Skin Diseases Interagency Coordinating
Committee for the National Institutes of Health held on January 10th
and 11, 1993.  The Workshop brought together a multidisciplinary
group of scientists working in the field of wound repair.  A summary
of this Workshop will be published in the Journal of Investigative
Dermatology.  Identified below is a selection of the areas covered in
that workshop that are relevant to this solicitation.  This list is
illustrative and not exclusive or restrictive.

Cytokines and Growth Factors

A number of reports have established that the application of growth
factors to acute experimental wounds in animals enhances healing.
However, it is unclear what role growth factors play in chronic
wounds.  Indeed, recent clinical trials of topical application of
single growth factors to pressure, venous and diabetic wounds have
not been very encouraging.  It should be appreciated that growth
factors are multifunctional with both stimulatory and inhibitory
actions depending upon cellular context.  Among the areas of interest
relative to cytokines and growth factors are:

o  What is the normal sequence of growth factors in acute wounds and
how are these altered in the chronic wound situation?

o  Are growth factors being trapped by macromolecules present in
chronic wounds?

o  Are growth factors released by cultured cells, both allogeneic and
autologous, that are applied to chronic wounds?

Keratinocyte Migration in the Wound Bed

In normal skin, the basal cells are attached to the basement membrane
and lose anchorage upon skin injury.  The signals responsible for
epidermal migration after wounding are unknown, but keratinocytes
begin to migrate toward the site of injury.  The "tractor tread"
hypothesis, whereby keratinocytes stop at the wound bed with
progressive climbing of proximal cells over the now resting cells has
gained wide acceptance as a model of keratinocyte migration.
Investigations of the epidermal edge of venous ulcers has shown that
the epidermis displays mitotic activity, resulting in increased
epidermal thickness at the edges of chronic wounds.  This has led to
the hypothesis that a fundamental defect exists in the chronic wound
situation, perhaps a failure of cells to adhere to one another or
their substrates.  There has been substantial recent information on
the signals for keratinocyte movement and substrate requirements at
least in the context of acute injury.  The concept that the
extracellular matrix is an integral part of keratinocyte migration
has also received experimental support.  Migration enhancing and
inhibiting molecules found in extracellular matrix and/or in wound
beds have been described.  Areas of research within this topic
include:

o  Investigations of specific cytokine and growth factor actions in
relation to keratinoctye migration;

o  Specific elucidation of the stimulatory and/or inhibitory effects
of the extracellular matrix molecules on keratinocyte migration;

o  Specific investigation of the basis for the failure of
keratinocytes to migrate across the bed of chronic wounds.

The Chronic Wound Environment

For the last several years, evidence has suggested that chronic
wounds may be growth factor deficient or represent a microenvironment
hostile to the repair process.  More recently, however, there is new
evidence suggesting that wounds may not necessarily be deficient in
growth factors, but that the stimulatory action of the peptides may
be prevented from being expressed.  Areas of inquiry in this subject
include:

o  Investigations of wound fluids from acute and chronic wounds to
establish whether or not there is a difference in regard to
stimulation and/or inhibition of the wound healing process;

o  Investigations designed to determine whether or not macromolecules
present in the chronic wound bed act as a trap for endogenous growth
factors, making them unavailable to the maintenance of tissue
integrity and the repair process at the wound site.

Matrix Degrading Metalloproteinases

Matrix degrading proteinases are proenzymes that need to be activated
and are considered to be the physiologic mediators of matrix
degradation.  The prototypic one is interstitial collagenase, but
there are at least ten of these enzymes that are secreted as
zymogens.  Stimulated by growth factors and by extracellular matrix,
they all utilize zinc with a zinc atom binding at the center of the
molecule at a conserved sequence.  They are stabilized by calcium and
inhibited by various chelators such as the tissue inhibitor of
metalloproteinase.  It is clear that collagenases are present in
acute wounds, but little or nothing is known about their possible
role in chronic wounds.  Within this area, research topics might
include:

o  Investigations of the source of metalloproteinases in acute and
chronic wounds;

o  Identification of which members of the metalloproteinase family
are present and in what sequence in both acute and chronic wounds;

o  Investigations of the role of the inhibitors of the
metalloproteinases in the wound healing process.

Metabolic Abnormalities

The incidence of chronic wounds appears to be higher in persons
suffering from disease conditions such as diabetes or physical
disabilities due to mobility impairments such as those that result
from spinal cord injury (SCI).  Little is known about how changes in
the homeostatic mechanisms of persons having either of these
conditions predispose them to wounds, or how they affect wound
repair.  Though the categories of chronic wounds that are prevalent
in both conditions vary, there may be similar etiologies.  For
diabetic wounds, both neurological abnormalities and vasculopathy
have been postulated in explaining the pathogenesis of the diabetic
ulcer.  In persons with SCI, changes in sensory innervation and
circulation provide a spectrum of metabolic changes that can
predispose to the development of chronic wounds.

In this area, further research could include:

o  Investigations of small vessel abnormalities as a contributor to
diabetic ulceration;

o  Investigations of the effect of neurotransmitters and
neuropeptides for their effect upon the inflammatory and wound
healing process;

o  Investigations of the effects of excess glucose or sorbitol on
cell metabolism in the context of wound repair.

Hypoxia

Oxygen plays a major role in wound repair and probably is a
fundamental aspect of chronic wound pathogenesis.  For the most part,
the biology of oxygen in wound healing has been studied in the
context of connective tissue synthesis.  Oxygen also has important
effects on a number of enzyme systems that can alter cell behavior.
In this subject area, further investigation would be possible in:

o  Effect of oxygen or lactate in the stimulation of extracellular
matrix and/or in the fibrotic reaction observed in some chronic
wounds;

o  The interaction of low oxygen tension with the release of various
growth factors and cytokines and their effect on the wound healing
process.

Fibrin Formation and Removal

Chronic wounds, including pressure ulcers and venous ulcers, are
characterized by the presence of fibrin within the wound bed and
surrounding tissues.  Fibrin accumulation in acute wounds is removed
within days, but it is not degraded in chronic wounds.  Knowledge of
the process of fibrin formation and polymerization that has
accumulated in recent years may provide the basis for understanding
the persistence of fibrin in chronic wounds.  The role of fibrin
retention and the adherence of other molecules to it in interacting
with cytokines and growth factors in the wound healing process have
just begun to be investigated.  In this area, new research approaches
could include:

o  Investigations of the process of fibrin accumulation in chronic
wounds;

o  Investigations of specific macromolecules that bind to fibrin in
the chronic wound bed and their influence on wound healing;

o  Investigations of the fibrin polymers seen in chronic wounds and
their comparison to that seen in acute wounds.

Aging and Chronic Wound Healing

It has been noted by many investigators that wound healing is slower
in older individuals, but the underlying cause and mechanism is not
understood.  Areas of interest include:

o  Changes in composition of extracellular matrix with advancing age;

o  Alterations in wound healing with advancing age.

Clinical Therapeutics

An important focus of wound healing research is the improvement of
patient care through the interdisciplinary collaboration between
clinicians and basic scientists.  Restoration of physical integrity
and function of the injured or diseased tissue can best be
accomplished by integrating bio/molecular technology with clinical
treatments as clinicians and basic scientists work together.
Examples to encourage opportunities for clinicians to collaborate
with basic scientists include:

o  Investigations designed to determine the biological or molecular
reason for successful wound healing with currently used clinical
therapies, such as electrical stimulation, laser, or nutritional
regimens.  For example, clinicians have reported faster healing of
pressure sores with patients on high protein diets.  In order to
identify the pivotal amino acid, methionine, cysteine, or arginine
might be studied.  Because zinc is a necessary cofactor of DNA
polymerase and reverse transcriptase, studies could be pursued to
determine whether or not the healing impairment associated with zinc
deficiency is due to an inhibition of cellular proliferation

o  Investigations designed to identify specific biological/molecular
markers that could be used to define standardized outcome measures.
For example, various dressings such as hydrocolloid, polyvinyldiene,
polyethylene, polyurethane, and human skin are used in health care
facilities to increase the rate of epithelial healing.  Can serum
protease inhibitors or tissue inhibitors be identified in the fluid
of chronic wounds to standardize use of specific wound cleansers and
dressings in the treatment of pressure sores/venous leg ulcers?

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women
in study populations so that research findings can be of benefit to
all persons at risk of the disease, disorder or condition under
study; special emphasis must be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to
apply to males and females of all ages.  If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear compelling
rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information must be included in the form PHS 398
(rev. 9/91) in Sections 1-4 of the Research Plan AND summarized in
Section 5, Human Subjects.  Applicants are urged to assess carefully
the feasibility of including the broadest possible representation of
minority groups.  However, NIH recognizes that it may not be feasible
or appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority populations
(i.e., Native Americans [including American Indians or Alaskan
Natives], Asian/Pacific Islanders, Blacks, Hispanics).

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including, but not limited to,
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of women applies fully;
since the definition of minority differs in other countries, the
applicant must discuss the relevance of research involving foreign
population groups to the United States' populations, including
minorities.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and reflected
in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

GENERAL CLINICAL RESEARCH CENTERS

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or Principal Investigator could be included
with the application.

LETTER OF INTENT

Prospective applicants are asked to submit, by October 15, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains allows ICD staff to estimate the potential review
workload and to avoid conflict of interest in the review.

The letter of intent is to be sent to Dr. Alan N. Moshell at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research; from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone 301/435-0714.

The RFA label available in the PHS 398 (rev. 9/91) application form
must be affixed to the bottom of the face page of the application.
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.  In addition, the RFA title and number must be typed on
line 2a of the face page of the application form and the YES box must
be marked.

Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, photocopies, in one package to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional copies of the application
must also be sent to Dr. Alan N. Moshell at the address listed under
INQUIRIES.

Applications must be received by November 30, 1993.  If an
application is received after that date, it will be returned to the
applicant without review.  The Division of Research Grants (DRG) will
not accept any application in response to this announcement that is
essentially the same as one currently pending initial review, unless
the applicant withdraws the pending application.  The DRG will not
accept any application that is essentially the same as one already
reviewed.  This does not preclude the submission of substantial
revisions of applications already reviewed, but such applications
must include an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the
DRG and responsiveness by the NIAMS.  Incomplete applications will be
returned to the applicant without further consideration.  If the
application is not responsive to the RFA, ICD staff will contact the
applicant to determine whether to return the application to the
applicant or submit it for review in competition with unsolicited
applications at the next review cycle.

Applications may be triaged by an ICD peer review group on the basis
of relative competitiveness.  The NIH will withdraw from further
competition those applications judged to be non-competitive for award
and notify the applicant Principal Investigator and institutional
official.  Those applications judged to be competitive will undergo
further scientific merit review.  Those applications that are
complete and responsive will be evaluated in accordance with the
criteria stated below for scientific/technical merit by an
appropriate peer review group convened by NIAMS.  The second level of
review will be provided by the National Advisory ICD Council/Board.

Review criteria for this RFA are generally the same as those for
unsolicited
research grant applications and include:

o  scientific, technical, or clinical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

o  responsiveness to the RFA objectives.

AWARD CRITERIA

The anticipated date of award is July 1, 1994.

Awards will be based upon the following criteria:

o  priority score
o  availability of funds
o  programmatic priorities of the funding ICD
o  responsiveness to the RFA

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Address the letter of intent and send two copies of the completed
application to:

Alan N. Moshell, M.D.
National Institute of Arthritis and Musculoskeletal and Skin Diseases
Westwood Building, Room 752
Bethesda, MD  20892
Telephone:  (301) 594-9955
FAX:  (301) 594-9673

Direct inquiries regarding programmatic issues to:

Hilary D. Sigmon, Ph.D., R.N.

National Institute for Nursing Research
Westwood Building, Room 405
Bethesda, MD  20892
Telephone:  (301) 594-7397
FAX:  (301) 594-7603

Dr. David Finkelstein
National Institute on Aging
Gateway Building, Room 2C231
Bethesda, MD  20892
Telephone:  (301) 496-6402
FAX:  (301) 402-0010

Dr. Danuta Krotoski
National Center for Medical Rehabilitation Research
National Institute of Child Health and Human Development
Building 61E, Room 2A03
Bethesda, MD  20892
Telephone:  (301) 402-2242
FAX:  (301) 402-0832

Dr. Charles A. Wells
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 622
Bethesda, MD  20892
Telephone:  (301) 594-7505
FAX:  (301) 594-9011

Direct inquiries regarding fiscal matters to:

Mary Graham
National Institute of Arthritis, Musculoskeletal and Skin Diseases
Westwood Building, Room 722
Bethesda, MD  20892
Telephone:  (301) 594-9974
FAX:  (301) 594-9950

Sally A. Nichols
Grants Management Office
National Institute for Nursing Research
Westwood Building, Room 748
Bethesda, MD  20892
Telephone:  (301) 594-7498
FAX:  (301) 594-7603

Mary Ellen Colvin
Grants Management Office
National Institute of Child Health and Human Development
Building 61E, Room 8A17F
Bethesda, MD  20892
Telephone:  (301) 496-1303
FAX:  (301) 402-0915

Bob Pike
Grants Management Office
National Institute on Aging
Gateway Building, Room 2N212
Bethesda, MD  20892
Telephone:   (301) 496-1472
FAX:  (301) 402-3672

Betty E. Bailey
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649
Bethesda, MD  20892
Telephone:  (301) 594-7543
FAX:  (301) 594-7594

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.361.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410, as
amended by Public Law 99-158, 42 USC 241 and 285) and administered
under PHS grants policies and Federal Regulations 42 CFR 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.

.

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