Full Text PA-96-055
 
SMALL MOLECULE TRANSPORTER PROTEINS IN BLOOD, RENAL AND PROSTATE CELLS
 
NIH GUIDE, Volume 25, Number 18, June 7, 1996
 
PA NUMBER:  PA-96-055
 
P.T. 34

Keywords: 
  Hematology 
  Biology, Cellular 
  Membrane Structure/Function 

 
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, supports fundamental and applied research aimed at
understanding the fundamental processes underlying the normal and
pathologic function of blood cells and the blood forming system.
Also supported is 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.
Urologic research is supported, including cellular and molecular
approaches to the study of tissue-specific and cell-specific
regulation of prostate growth.
 
The ability to maintain a constant systemic environment is a critical
requirement to maintain the normal health of an organ.  At the
cellular level, specific transport pathways maintain both the
intracellular environment as well as providing the mechanisms that
drive the maintenance of systemic balance.  Cellular transport is
mediated by specific membrane proteins.  To understand the physiology
and pathophysiology of homeostatic balance requires an understanding
of how they are regulated.  Methods for identifying and isolating the
proteins or the genes for the proteins are available using
contemporary cellular and molecular biological approaches.  Such
approaches have been used successfully to isolate a number of
transporters from kidney, prostate, red blood cells, and other cells,
making it possible to understand normal homeostatic mechanisms, as
well as those leading to pathology of the homeostatic system.
 
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 proposed 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
 
Examples of applications responsive to the announcement include:  (1)
development of integrated programs to study the structure and
function of the different transport proteins that are expressed in
the red cell, prostate, and the kidney; (2) molecular biological
approaches to study tissue specific expression of the various
isoforms of the proteins; (3) development of information on
structural biology of the proteins; (4) immunochemical localization
of different proteins in various blood, renal and prostatic cells;
(5) functional analysis of the proteins using tissue-specific
knockout strategies; (6) definition of mutations responsible for
human diseases; (7) definition of the functional consequences of
protein-protein interactions in the membrane, and of membrane
protein-cytoskeletal interactions; (8) the study of lipid-protein
interactions, such as membrane microdomains; and (9) the study of the
regulation of transport protein function by accessory molecules that
act as regulators of these transporters under various
pathophysiological conditions.
 
Fundamental information has been accumulated on the molecular
architecture of the red cell membrane skeleton. It is becoming
increasingly clear that red cell structural proteins and their
isoforms are present in a wide variety of cells, including epithelial
and endothelial cells.  Knowledge of the dynamics of protein-protein
interactions in the red cell membrane is likely to contribute to our
understanding of the structure and function of plasma membranes of
nucleated cells.  Red cell blood group antigens are epitopes on
membrane-spanning proteins whose functions may include anion exchange
(Band 3--ABH antigens and Diego antigens), water transport (Colton
antigens), urea transport (Kidd antigens), degradation of circulating
peptide hormones (Kell antigens), removal of circulating chemokines
(Duffy antigens), or possibly provision of structural supports for
localized lipid environments (Rh antigens).  Several of these
proteins have been identified also in renal tubules.  There also has
been a recent rapid increase in information on the identification and
isolation of small molecule transporters in kidney and similar
epithelia. Some examples are the Na/Cl and Na/K/Cl cotransporters,
Na, K, and Ca channels, N/H antiporters, hormone receptors in the
prostate, and Na/Cl exchangers.
 
An integrated approach linking the biochemical and molecular genetic
information derived from red cell studies with the sophisticated
physiological analyses of microdissected renal tubules and highly
resolved distributional studies in kidney and prostate are likely to
provide major insight into this new area of biology. Moreover,
detailed molecular and clinical analysis of human null phenotypes of
each of these antigenic groups may be very instructive, since many
could turn out to be equivalent to gene knockouts.
 
Similarly, knowledge derived from study of white blood cells offers
the opportunity to learn more about transport functions, signal
transduction, membrane-trafficking, cell transfection (particularly
in lymphocytes), genetic diseases, and adhesion molecules.
 
Interaction of investigators with expertise in blood cell membrane
physiology and investigators in kidney and/or prostate epithelial
cell biology is particularly encouraged.
 
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 28, 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
 
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the 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:
asknih@odrockm1.od.nih.gov.
 
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.
 
Potential R29 applicants should refer to the announcement on
Just-in-Time Procedures for FIRST and Career Awards (NIH Guide for
Grants and Contracts, Vol. 25, No. 10, March 29, 1996)) for
information on recent changes in guidelines for FIRST award format.
 
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
 
Although this is a Program Announcement sponsored by the National
Institute of Diabetes and Digestive and Kidney Diseases, the National
Heart, Lung, and Blood Institute also has an interest in the subject
matter of this PA.  Other Institutes/Centers of the NIH also may have
an interest.  Applications will be assigned to the most appropriate
Institute/Center 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.  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:
 
David G. Badman, Ph.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room AS-13C MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7717
FAX:  (301) 480-3510
Email:  David_Badman@nih.gov
 
Inquiries regarding fiscal matters may be directed to:
 
Aretina Perry
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AN-38B, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8862
Email:  PerryA@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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