Full Text PA-97-099
 
GENES AND MECHANISMS UNDERLYING PRIMARY IMMUNODEFICIENCY
 
NIH Guide, Volume 26, Number 29, August 29, 1997
 
PA NUMBER:  PA-97-099
 
P.T.


Keywords: 

 
National Institute of Allergy and Infectious Diseases
National Institute of Child Health and Human Development
 
PURPOSE
 
The National Institute of Allergy and Infectious Diseases (NIAID) and
the National Institute of Child Health and Human Development (NICHD),
National Institutes of Health (NIH), invite applications for research
studies to:  identify and characterize genes that cause primary
immunodeficiency diseases; characterize the molecular mechanisms
involved in primary immunodeficiency diseases which are not the
result of a single defective gene; identify the immunologic role of
defective gene products and their normal counterparts; and, based on
this knowledge, develop more effective approaches for the diagnosis,
treatment, and prevention of these disorders.
 
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 Program
Announcement, "GENES AND MECHANISMS UNDERLYING PRIMARY
IMMUNODEFICIENCY", is related to the priority areas of Maternal and
Infant Health and Diabetes and Chronic Disabling Diseases.  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
 
Applications may be submitted by 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.  Domestic and foreign
institutions are eligible to apply for R01 grants.  Domestic
institutions are eligible for First Independent Research Support and
Transition Award (FIRST)(R29) grants.  Foreign institutions are not
eligible for FIRST award (R29) grants. Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.
 
MECHANISMS OF SUPPORT
 
Mechanisms supported by NIAID and NICHD in this PA are the
traditional research project grant (R01) and the FIRST award (R29)
grant.  Applications for R01 grants may request up to five (5) years
of support, however, foreign application may not request more than 3
years of support; applications for R29 grants must request five years
of support.  Responsibility for the planning, direction, and
execution of the proposed research for all applicable mechanisms of
support will be solely that of the applicant.
 
RESEARCH OBJECTIVES
 
Background
 
Primary immunodeficiency diseases are a heterogeneous group of
diseases all of which are characterized by an immune system
dysfunction that is responsible for clinical features such as
increased susceptibility to infection and abnormal inflammatory
responses.  There are more than 70 such diseases (e.g., Wiskott-
Aldrich Syndrome, Ataxia-telangiectasia, Bare Lymphocyte Syndrome).
Although many are rare it has been estimated that as many as 500,000
individuals in the United States are affected, of whom 5,000-10,000
(many of them children) are severely affected.  The causative genes
and pathogenic mechanisms for many of these diseases have not been
identified.  Morbidity, mortality, medical and social costs for
severely affected individuals and their families are extremely high.
 
Remarkable progress has been made in the identification and cloning
of genes which cause primary immunodeficiency diseases.  These
include: 1)  X-linked Agammaglobulinemia, an antibody deficiency
disease in which all classes of antibody are low or absent; the
defective gene encodes Btk, an enzyme found in the cytoplasm of B
lymphocytes; 2)  X-linked Severe Combined Immunodeficiency, an
immunodeficiency in which both cellular and humoral immunity are
deficient; the defective gene encodes the common gamma chain of many
of the cytokine receptors on T lymphocytes; 3) X-linked Hyper-IgM
Syndrome in which IgM antibodies are normal or elevated but IgG and
IgA are low or absent; the defective gene encodes a protein expressed
on activated T lymphocytes called CD40 ligand; 4)  Wiskott-Aldrich
Syndrome, an immunodeficiency involving T and B lymphocytes and
platelets; the defective gene encodes a previously unknown protein
whose function is not yet known; and 5)  Chronic Granulomatous
Disease in which patients suffer from defective neutrophil function;
the defective genes encode proteins which are important for the
production of microbicidal oxidants.
 
Research Objectives and Scope
 
The research objectives of this PA are to:  identify and characterize
genes that cause primary immunodeficiency diseases; characterize the
molecular mechanisms involved in primary immunodeficiency diseases
which are not the result of a single defective gene, identify the
immunologic role of defective gene products and their normal
counterparts; and, based on this knowledge, develop more effective
approaches for the diagnosis, treatment, and prevention of these
disorders.
 
The identification of the genes described in the background section
provides the opportunity for detailed evaluation of the roles that
the products of these genes play in normal immune system function.
Progress in genome mapping and the application of positional cloning
techniques provide the opportunity to identify and characterize the
genetic defects in additional disorders.  For disorders which are not
caused by a single genetic defect, advances in the understanding of
the molecular mechanisms of immunity provide opportunities for
characterization of the pathogenic mechanisms.
 
Research topics of interest include, but are not limited to, the
following:
 
Identification of previously unidentified defective  single genes
which cause primary immunodeficiency  e.g., X-linked
Lymphoproliferative Syndrome, Chediak- Higashi Syndrome)
 
Characterization of the molecular mechanisms involved  in the
pathogenesis of immunodeficiency diseases which  are not the result
of a single defective gene (e.g.,  Common Variable Immunodeficiency)
 
Characterization of the immunologic role of genes whose  defects
cause primary immunodeficiency, including  cellular expression,
ligands, signaling pathways and  molecular interactions
 
Delineation of the mechanisms for associated clinical  abnormalities
not apparently explained by the known  genetic defect (e.g.
neutropenia in Hyper IgM Syndrome)
 
Identification of genetic and other factors which  result in
different levels of severity by exacerbating  or compensating for the
mutations in these genes
 
Characterization of the transcriptional regulation of  the defective
genes
 
Characterization of the defective genes in mouse models  of
immunodeficiency
 
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 are
provided that inclusion is inappropriate with respect to the health
of the subjects of the purpose of the research.  This policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43). 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
14508-14513) and the NIH Guide for Grants and Contracts, Vol. 23, No.
11, March 18, 1994.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application for PHS 398
(rev. 5/95) and will be accepted on the standard application
deadlines as indicated on the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC
7910, Bethesda, MD 20892-7910, telephone (301) 710-0267, email:
[email protected].
 
For purposes of identification and processing, item 2 on the face
page of the application must be marked "YES".  The PA number and the
PA title must also be typed in section 2.
 
The completed, signed original and five legible, single-sided copies
of the application 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 20817-7710 (for express/courier service)
 
R29 applications must include at least three (3) sealed letters of
reference attached to the face page of the original application.
FIRST applications submitted without the required number of reference
letters will be considered incomplete and will be returned without
review.
 
Applicants from institutions that have a General Clinical Research
Centers (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the Center as a resource for
conducting the proposed research.  If so, a letter of agreement from
the GCRC Program Director must be included in the application
material.
 
REVIEW CONSIDERATIONS
 
Review Procedures
 
Applications will be assigned on the basis of established PHS
referral guidelines. Upon receipt, applications will be reviewed for
completeness by the NIH Division of Research Grants.  Incomplete
applications will be returned to the applicant without further
consideration.  Applications will be reviewed for scientific and
technical merit by study sections of the Division of Research Grants,
NIH, in accordance with the standard 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 the applications under review, will be discussed,
assigned a priority score, and receive a second level review by the
appropriate national advisory council.
 
Review Criteria
 
The five criteria to be used in the evaluation of grant applications
are listed below.  To put those criteria in context, the following
information is contained in instructions to the peer reviewers.
 
The goals of NIH-supported research are to advance our understanding
of biological systems, improve the control of disease, and enhance
health.  The reviewers will comment on the following aspects of the
application in their written critiques in order to judge the
likelihood that the proposed research will have a substantial impact
on the pursuit of these goals.  Each of these criteria will be
addressed and considered by the reviewers in assigning the overall
score weighting them as appropriate for each application.  Note that
the application does not need to be strong in all categories to be
judged likely to have a major scientific impact and thus deserve a
high priority score.  For example, an investigator may propose to
carry out important work that by its nature is not innovative but is
essential to move a field forward.
 
1.  Significance.  Does this study address an important problem? If
the aims of the application are achieved, how will scientific
knowledge be advanced?  What will be the effect of these studies on
the concepts or methods that drive this field?
 
2.  Approach.  Are the conceptual framework, design, methods, and
analyses adequately developed, well-integrated, and appropriate to
the aims of the project?  Does the applicant acknowledge potential
problem areas and consider alternative tactics?
 
3.  Innovation.  Does the project employ novel concepts, approaches
or method?  Are the aims original and innovative? Does the project
challenge existing paradigms or develop new methodologies or
technologies?
 
4.  Investigator.  Is the investigator appropriately trained and well
suited to carry out this work?  Is the work proposed appropriate to
the experience level of the principal investigator and other
researchers (if any)?
 
5.  Environment.  Does the scientific environment in which the work
will be done contribute to the probability of success?  Do the
proposed experiments take advantage of unique features of the
scientific environment or employ useful collaborative arrangements?
Is there evidence of institutional support?
 
The initial review group will also examine: the appropriateness of
proposed project budget and duration; the adequacy of plans to
include both genders and minorities and their subgroups as
appropriate for the scientific goals of the research and plans for
the recruitment and retention of subjects; the provisions for the
protection of human and animal subjects; and the safety of the
research environment.
 
AWARD CRITERIA
 
Applications will compete for available funds with all other
favorably recommended applications.  The following will be considered
when making funding decisions: quality of the proposed project as
determined by peer review, program balance, and availability of
funds.
 
INQUIRIES
 
Written and telephone inquiries are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
 
Inquiries regarding programmatic (research scope and eligibility)
issues may be directed to:
 
Howard B. Dickler, M.D.
Chief, Clinical Immunology Branch
Division of Allergy, Immunology, and Transplantation National
Institute of Allergy and Infectious Diseases Solar Building, Room
4A-19
6003 Executive Blvd.
Bethesda, MD 20892-7640
Telephone: (301) 496-7104
FAX:  (301) 402-2571
EMAIL:  [email protected]
 
Allan Lock, D.V.M.
Health Science Administrator
Developmental Biology, Genetics and Teratology Branch Center for
Research for Mothers and Children
National Institute of Child Health and Human Development Building
61E, Room 4B01B
6100 Executive Boulevard
Bethesda, MD 20892-7510
Telephone: (301) 496-5541
FAX:  (301) 402-4083
EMAIL:  [email protected]
 
Direct inquiries regarding fiscal matters to:
 
Maryellen Connell
Grants Management Branch
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases Solar Building,
Room 4B-28
6003 Executive Blvd.
Bethesda, MD 20892-7610
Telephone: (301-402-5576)
Fax: (301-480-3780)
Email: [email protected]
 
or
 
Douglas Shawver
Grants Management Branch
National Institute of Child Health and Human Development Building
61E, Room 8A17 MSC-7510
6100 Executive Boulevard
Bethesda, MD 20892-7510
Telephone: (301) 496-1303
FAX:  (301) 402-0915
EMAIL:  [email protected]
 
AUTHORITY AND REGULATIONS
 
This program is supported under authorization of the Public Health
Service Act, Sec. 301(c), Public Law 78-410, as amended.  The
Catalogue of Federal Domestic Assistance Citations are No. 93.855 -
Immunology, Allergy, and Transplantation Research and No. 93.865 -
Research for Mothers and Children.  Awards will be 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 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 the PHS
mission to protect and advance the physical and mental health of the
American people.
 
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