Full Text PA-96-029
 
RENAL FILTRATION BARRIER AND ITS CELLULAR COMPONENTS
 
NIH GUIDE, Volume 25, Number 4, February 16, 1996
 
PA NUMBER:  PA-96-029
 
P.T. 34

Keywords: 
  0715133 
  Biology, Cellular 

 
National Institute of Diabetes and Digestive and Kidney Diseases
 
PURPOSE
 
The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), through its Division of Kidney, Urologic and Hematologic
Diseases is the principal agency that supports fundamental and
applied research directed at normal renal structure, function and
regulation.  This includes studies utilizing whole kidney and/or the
selected segments of the kidney or individual cells or any of their
subcellular components as models.
 
The purpose of this program announcement is to stimulate research on
the glomerular portion of the nephron, with special emphasis on the
glomerular capillary wall and its cellular constituents, namely, the
glomerular endothelial and epithelia (podocytes) and the glomerular
basement membrane (GBM).  Although a third cell type, the mesangial
cell, is usually not considered a member of the glomerular wall
proper, it may influence the functions and dimensions of the wall and
transiently migrate onto or into the wall.  Also, glomerular
capillary morphogenesis is highly complex, involving mediators that
are present in the developing kidney and within renal epithelial
cells undergoing differentiation, which need to be explored to
provide new insights into the fundamental mechanisms that result in
the formation of glomerular capillaries in vivo.
 
Numerous observational and experimental studies have shown that
disruptions in glomerular cell shape and adherence and/or GBM
composition result in loss of valuable plasma constituents to urine.
Virtually every example of proteinuria in humans can be traced to
morphologic abnormalities in the glomerular wall.  The interactive
play among receptors, modulatory proteins, phospholipid metabolites
and second messengers is now becoming clearer in the modulation of
cytoskeletal organization, and growth and differentiation of the
kidney.  There are now cellular and molecular biologic techniques
that make it possible to identify and clone genes and proteins to
further expand research activity on the glomerulus.
 
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.  Potential
applicants may obtain a copy of "Healthy People 2000 (Full Report:
Stock No. 017-001-00474-0 or Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800).
 
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.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as principal investigators.
 
MECHANISM OF SUPPORT
 
This PA will use the National Institutes of Health (NIH) individual
research project grant (R01) and FIRST (R29) award mechanisms.
Responsibility for planning, direction, and execution of the proposed
project will be solely that of the applicant.  Because the nature and
scope of the research proposal in response to this PA may vary, it is
anticipated that the size of an award will vary also; however, the
support of requests exceeding the NIDDK average grant size of
$160,000 direct cost for R01 grants would be unusual and require
ample justification.  FIRST (R29) awards are limited to $350,000
direct cost over the five year period.
 
RESEARCH OBJECTIVES
 
Investigations are needed that will lead to functional connections
between existing fundamental knowledge gained from physiological
studies and information yet to be obtained by utilizing cell and
molecular biological techniques to directly address the
pathophysiology of the glomerular portion of the nephron.  Examples
of diseases with disorders of the renal filtration barrier include:
glomerulonephritis, Alport's disease, hypertension, and diabetic
nephropathy.
 
Responding applications should emphasize mechanisms rather than mere
descriptions of processes. State-of-the-art biochemistry, and
cellular and molecular biological techniques should be utilized in
such investigations.
 
The following are examples of projects/topics that would be
responsive, but are not meant to present the full range of
possibilities:
 
o  Studies that will provide an understanding of the maintenance of
the differentiated phenotype by glomerular cells, mesangial cells and
podocytes;
 
o  Receptor and mRNA localization studies on specific structures
within the juxtaglomerular apparatus (macula densa, granular cells,
etc.), especially not readily discernable or carefully probed in most
autoradiographic or immunocytochemical studies;
 
o  Studies that will delineate more precisely the lineages of the
glomerular endothelial and mesangial cells and podocytes;
 
o  Studies to delineate the relationship of cell-shape and basement
membrane attachments in gene activation and maintenance of structural
integrity capillary wall;
 
o  Studies to address transcriptional controls (both activation and
deactivation) of basement membrane genes by glomerular cells;
 
o  Studies that will illuminate mechanisms of assembly of
extracellular matrix molecules into the GBM, and mechanisms of GBM
turnover;
 
o  Studies that will provide insight into the establishment of the
glomerular microvasculature during organogenesis;
 
o  Studies that will provide new information concerning the
mechanisms of mesangial matrix catabolism and its regulation;
 
o  Studies to delineate the role of growth factors, cytokines and
hormones on the various glomerular cellular entities and GBM;
 
o  Studies to determine the acquisition of glomerular permselective
sieving properties, and the relative contribution of endothelial and
epithelial cells of these properties;
 
o  Studies on sex hormones and their receptors that may establish the
mechanisms of gender based differences in glomerular cell biology and
risk for glomerular disease;
 
o  Studies that will improve an understanding of the responses of
glomerular cells and GBM to immune- and non-immune-mediated injury.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations), which
have been in effect since 1990.  The new policy contains some
provisions that are substantially different from the 1990 policies.
 
All investigators proposing research involving human subjects should
read the "NIH Guidelines For Inclusion of Women and Minorities as
Subjects in Clinical Research," which have been published in the
Federal Register of March 20, 1994 (FR 59 1450814513) and reprinted
in the NIH Guide for Grants and Contracts, Volume 23, Number 11,
March 18, 1994.
 
Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
 
ANIMAL WELFARE CONSIDERATIONS
 
Investigators are encouraged to consider alternative methods and
approaches in their research grant applications that do not require
the use of whole animals, use alternative species such as nonmammals
or invertebrates, reduce the number of animals required, and
incorporate refinements to procedures that will result in the
elimination or further minimization of pain and distress in animals.
 
APPLICATION PROCEDURES
 
The research grant application form PHS 398 (rev. 5/95) is to be used
in applying for these grants.  Applications kits are available at
most institutional offices of sponsored research and may be obtained
from the Grants Information Office, Office of Extramural Outreach and
Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-0714,
email:  girg@drgpo.drg.nih.gov.
 
The RFA label available in the PHS 398 (rev. 5/95) 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 program announcement title and number
must be typed on line 2 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.
 
The completed original application and five legible copies must be
sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
 
REVIEW CONSIDERATIONS
 
Applications will be assigned on the basis of established Public
Health Service referral guidelines.  Applications that are complete
will be evaluated for scientific and technical merit by an
appropriate peer review group convened in accordance with NIH peer
review procedures. As part of the initial merit review, all
applications will receive a written critique and undergo a process in
which only those applications deemed to have the highest scientific
merit, generally the top half of applications under review, will be
discussed, assigned a priority score, and receive a second level
review by the appropriate national advisory council or board.
 
Review Criteria
 
o  scientific, technical, or medical 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  adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects, and the safety of the
research environment.
 
For Applications from Foreign Organizations:
 
o  availability of special opportunities for furthering research
programs through the use of unusual talent resources, populations, or
environmental conditions in other countries that are not readily
available in the United States or that provide augmentation of
existing U.S. resources.
 
AWARD CRITERIA
 
Applications will compete for available funds with other approved
applications assigned to the National Institute of Diabetes and
Digestive and Kidney Diseases.  The following will be considered in
making funding decisions:
 
o  Quality of the proposed project as determined by peer review;
o  Availability of funds;
o  Program priority.
 
INQUIRIES
 
Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome. Direct inquiries
regarding programmatic issues to:
 
M. James Scherbenske, Ph.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6As.19E MSC 6600
BETHESDA, MD  20892-6600
Telephone:  (301) 594-7719
FAX:  (301) 480-3510
Email:  scherbensk@ep.niddk.nih.gov
 
Inquiries regarding fiscal matters may be directed to:
 
Helen Y.S. Ling
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6An.44F, MSC 6600
BETHESDA, MD  20892-6600
Telephone:  (301) 594-8857
Email: lingh@ep.niddk.nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.849.  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.
 
The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine education,
library, day care, health care or early childhood development
services are provided to children. This is consistent with PHS
mission to protect and advance the physical and mental health of the
American people.
 
.

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