NONHUMAN PRIMATE MODELS OF HIV-ASSOCIATED PULMONARY, CARDIOVASCULAR,
AND HEMATOLOGICAL DISORDERS
RELEASE DATE: December 4, 2002
RFA: HL-03-005
National Heart, Lung, and Blood Institute (NHLBI)
(http://www.nhlbi.nih.gov)
LETTER OF INTENT RECEIPT DATE: February 20, 2003
APPLICATION RECEIPT DATE: March 20, 2003
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Research Objectives
o Mechanism(s) of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations:
PURPOSE OF THIS RFA
The National Heart, Lung, and Blood Institute (NHLBI) invites
applications on the use of nonhuman primate models for the study of
Human Immunodeficiency Virus (HIV)-associated pulmonary,
cardiovascular, and hematologic disorders. These primate models
(e.g., Simian Immunodeficiency Virus [SIV]- and Simian-Human
Immunodeficiency Virus [SHIV]-infected monkeys) should be designed to
facilitate the study of the biological and clinical characteristics of
disorders of lung, heart, blood, and bone marrow, associated with HIV
infections and co-infections as well as to evaluate novel methods for
prevention and treatment of these conditions.
RESEARCH OBJECTIVES
Background
HIV infection results in progressive damage of the immune system of
infected individuals and makes them susceptible to a wide variety of
opportunistic (bacterial, viral, fungal, and protozoan) infections.
Lung infections that occur in patients during the course of HIV
infection and AIDS (prominently among them, tuberculosis) represent a
major cause of morbidity and mortality for HIV-infected individuals
around the world. Dual infection and synergism between HIV and
Mycobacterium tuberculosis (Mtb) represent a worldwide health crisis
affecting millions of people, especially in developing nations in
Africa and Asia. Each year an estimated 8 million people develop
clinical tuberculosis and the annual death toll from this disease is
estimated at 2 to 3 million people. The majority of tuberculosis cases
occur in the same populations in which there are also millions of cases
of HIV infection. Individuals infected with HIV are far more
susceptible to Mtb infection than those without HIV infection.
Therefore, dual HIV-Mtb infections in humans are extremely common and
their clinical course is more severe and more rapidly fatal. Likewise,
infection with Mtb increases HIV production in patients with dual HIV-
Mtb infections and hastens the progression of AIDS and other HIV-
related diseases. The concurrent presence of infections other than
tuberculosis in the lungs of humans, such as Pneumocystis carinii
pneumonia and pneumococcal pneumonia, can also increase the replication
of HIV and accelerate the course of AIDS. HIV-associated immune
dysfunction increases the likelihood and severity of these lung
infections and also appears to alter the pathogenesis and clinical
course of these respiratory infections in ways that are different from
other immunodeficient conditions. By altering local immunity in the
lung, HIV infection can also result in harmful inflammatory responses
and infiltrates that may cause acute or chronic lung injury (e.g., HIV-
associated emphysema and pulmonary hypertension).
In the era prior to availability of highly active antiretroviral
therapy, cardiac involvement in HIV disease was estimated to be
approximately 6-7%. Autopsy series and retrospective analyses suggest
that cardiac lesions are present in 25-75% of patients with AIDS. HIV-
related cardiovascular diseases include pericardial effusion,
myocarditis, dilated cardiomyopathy, endocarditis, atherosclerosis,
hypertension, malignant neoplasms and drug-related cardiotoxicity.
Contributory roles of the HIV virus itself, the extent of
immunodeficiency, and the existence of co-infection in the pathogenesis
of HIV-associated cardiovascular disorders are not well defined.
Furthermore, other factors such as inflammation, nutritional
deficiencies, autoimmune responses, and pharmacologic effects of anti-
retroviral agents warrant exploration in the context of HIV-related
cardiovascular disorders. SIV- and SHIV-infected non human primates
provide an opportunity for in-depth, controlled study of these matters.
Blood- and marrow-related disorders have been observed in SIV-infected
monkeys, and parallel findings have been found in humans infected with
HIV. Therefore, the nonhuman primate model system is useful for
furthering our understanding of the mechanism(s) associated with these
disorders and for exploring strategies for prevention and treatment.
Hematopoietic abnormalities associated with HIV infection include:
decreased proliferation of hematopoietic stem and progenitor cells,
increased destruction of mature cells, and alterations in the
supportive marrow stromal environment and in the production of
regulatory cytokines. The pathophysiologic mechanisms of these
abnormalities are poorly understood and require study. Also, it is
known that thrombocytopenia is one of the earliest manifestations of
HIV infection in human and primates. HIV infection of humans is likely
to bring about changes in the functions of cytokines and matrix
proteins, in the migration of megakaryocytes, and in the production and
destruction of platelets (which can lead to development of
thrombocytopenia).
Many opportunistic infections involve pathogenic agents that encode and
express proteins that, in turn, modulate host immune responses. The
synergism of these molecules during co-infection may profoundly alter
lymphoid cell trafficking, signaling, and function. These effects may
have profound implications on homeostatic regulation of the heart,
lung, and bone marrow. The roles that dendritic cells play in the
initial systemic infection by virus, in the induction of humoral and
cell-mediated immunities, and in the development of local immunity need
to be actively investigated.
Objective and Scope
Since the discovery of the SIV in 1984, the disease that occurs in
experimentally infected nonhuman primates (i.e., simian AIDS) has been
extensively investigated and is considered a useful model for the study
of human AIDS. This model has been utilized to assess HIV
pathogenesis, to validate therapies, and to develop and test AIDS
vaccines.
Through this initiative, we wish to stimulate collaborations among
scientists devoted to studies of SIV/SHIV disease in primates as a
model for human AIDS, and investigators with expertise and experience
in the following fields of relevant research: studies of tuberculosis,
Pneumocysis carinii pneumonia, pneumococcal pneumonia, and other
pulmonary and cardiovascular infections/disorders and studies of the
roles of blood cellular components in the genesis and progression of
AIDS. Such collaborations should take advantage of the large wealth of
knowledge and resources (e.g., biological and immunologic reagents)
that have been generated during the past 15 years.
Some examples of research topics that will be considered responsive to
this RFA include, but are not limited to:
o Analysis of local immunological status, and heart or lung pathology,
in the course of acute and chronic SIV/SHIV infection and simian AIDS
o Research to elucidate the mechanism(s) of cardiac ventricular
dysfunction associated with HIV infection
o The study of SIV/SHIV-Mtb co-infections aimed at the understanding of
their molecular and biological interactions and their synergistic
effect(s) on the lung immune system
o Research to determine the mechanism by which Tumor Necrosis Factor-
alpha (TNF-alpha) inhibitors, used for the management of diseases like
rheumatoid arthritis and Crohn's disease, can re-activate latent Mtb
infection and promote the development of extrapulmonary tuberculosis
o Analysis of the status of the different bone marrow components during
the course of SIV/SHIV infection and progression to simian AIDS
MECHANISM OF SUPPORT
This RFA will use the R01 (investigator-initiated research project
grant) award mechanism. As an applicant, you will be solely
responsible for planning, directing, and executing the proposed
project. This RFA is a one-time solicitation. Future unsolicited,
competing-continuation applications based on this project will compete
with all investigator-initiated applications and will be reviewed
according to the customary peer review procedures. The anticipated
award date is September 30, 2003.
This RFA uses just-in-time concepts (e.g., for documentation of
appropriate animal welfare requirements). It also uses the modular as
well as the non-modular budgeting formats (see
https://grants.nih.gov/grants/funding/modular/modular.htm).
Specifically, if you are submitting an application with direct costs in
each year of $250,000 or less, use the modular format. Otherwise,
follow the instructions for non-modular research grant applications.
Since the total costs for a subcontract or consortium are included in
the direct cost request, one additional module of $25,000 above the cap
may be requested for the facilities and administrative costs associated
with third party agreements A module requested for this purpose must be
clearly identified in the budget justification section of the
application, and will be restricted for this purpose only at the time
of award.
FUNDS AVAILABLE
The NHLBI intends to commit approximately $3.8M in FY 2003 to fund five
to seven new and/or competitive continuation grants in response to this
RFA. An applicant may request a project period of up to 5 years and a
budget for direct costs of up to $500,000 per year. We recognize that
a dramatic shortage of primates available for research exists at
present in this country; because of this, collaborations with
institutions outside of the United States may be considered. Because
the nature and scope of the proposed research will vary from
application to application, it is anticipated that the size and
duration of each award will also vary. Although the financial plans of
the NHLBI provide support for this program, awards pursuant to this RFA
are contingent upon the availability of funds and the receipt of a
sufficient number of meritorious applications.
Although interested in this area of research, the National Institute of
Allergy and Infectious Diseases (NIAID) is not participating in this
initiative.
ELIGIBLE INSTITUTIONS
You may submit (an) application(s) if your institution has any of the
following characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges,
hospitals, and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign
o Faith-based or community-based organizations
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to
carry out the proposed research is invited to work with their
institution to develop an application for support. Individuals from
under-represented racial and ethnic groups as well as individuals with
disabilities are always encouraged to apply for NIH programs.
SPECIAL REQUIREMENTS
Inclusions
o Optimal utilization of the resources generated under this RFA is
strongly recommended; therefore, a plan for proper acquisition and
storage of non human primate tissue, to be made available to interested
and qualified investigators for further study, is required as part of
the application. Investigators should include a request for funds in
the budget for this purpose.
o Furthermore, investigators should indicate their willingness to
participate in a meeting to determine how to standardize tissue
collection and storage and to develop criteria for fair distribution of
the samples; funds should be set-aside for this purpose.
o The applicants should also state their willingness to provide
detailed descriptions of protocols and phenotypes.
o To be responsive to this announcement, applications must propose
collaborations between scientists devoted to studies of SIV/SHIV
disease in primates, as a model for human AIDS, and investigators who
are documented experts in lung, cardiovascular, or blood diseases.
Exclusions
o Applications that lack a statement of willingness to share tissues and
data with other investigators.
o The establishment of new primate facilities will not be supported by
this RFA.
Grantees' Meetings
Upon initiation of the program, the NHLBI will sponsor annual meetings
to encourage exchange of information and dissemination of results among
investigators who participate in this program. In their budgets,
applicants should include funds for annual one-day grantees' meetings,
to be held, most likely, in Bethesda, Maryland. Applicants should also
include a statement in their applications that indicates their
willingness to participate in these meetings.
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this RFA and we welcome the
opportunity to answer questions from potential applicants. Inquiries
may fall into three areas: scientific/research, peer review, and
financial or grants management issues.
Please direct your questions about scientific/research issues to:
Sandra Colombini Hatch, M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7956
Bethesda, MD 20892-7956
Telephone: (301) 435-0222
FAX: (301)-480 3557
Email:hatchs@nhlbi.nih.gov
Luiz Barbosa Ph.D.
Division of Blood Disease Research
National Heart Lung and Blood Institute
6701 Rockledge Drive, MSC 7950
Bethesda, MD 20892-7950
Telephone: (301) 435-0075
Fax: (301) 480-0868
Email: barbosal@nhlbi.nih.gov
Diane Reid M.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7940
Bethesda, MD 20982-7940
Telephone: (301) 435-0515
Fax: (301) 480-1336
Email: reidd@nhlbi.nih.gov
Please direct your questions about peer review issues to:
Anne P. Clark, Ph.D.
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive 7214, MSC 7924
Bethesda, MD 20892-7924 (20817 for express/courier service)
Telephone: (301)435-0270
FAX: (301)480-0730
Email: clarka@nhlbi.nih.gov
Please direct your questions about financial or grants management
matters to:
Robert A. Pike
Division of Extramural Affairs
Grant Operation Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive 7214, MSC 7924
Bethesda, MD 20892-7924 (20817 for express/courier service)
Telephone: (301) 480-0182
FAX: (301) 4803310
Email: PikeR@nhlbi.nih.gov
LETTER OF INTENT
Prospective applicants are asked to submit a letter of intent that
includes the following information:
o Descriptive title of the proposed research;
o Name, address, telephone number, and e-mail address of the Principal
Investigator;
o Names of other key personnel;
o Participating institutions; and
o Number and title of this RFA
Although a letter of intent is not a requirement, is not binding, and
does not enter into the review of a subsequent application, the
information that it contains allows IC staff members to estimate the
potential review workload and to plan the review. Letters of intent
should be sent by the date listed at the beginning of this document to
Dr. Anne Clark at the address listed under WHERE TO SEND INQUIRIES.
SUBMITTING AN APPLICATION
Applications must be prepared using the PHS 398 research grant
application instructions and forms (rev. 5/2001). The PHS 398 is
available at https://grants.nih.gov/grants/funding/phs398/phs398.html in
an interactive format. For further assistance contact GrantsInfo,
Telephone (301) 710-0267, E-mail: GrantsInfo@nih.gov.
SUPPLEMENTAL INSTRUCTIONS:
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS:
Applications requesting up to $250,000 per year in direct costs must be
submitted in a modular grant format. The modular grant format
simplifies the preparation of the budget in these applications by
limiting the level of budgetary detail. Applicants request direct
costs in $25,000 modules. Section C of the research grant application
instructions for the PHS 398 (rev. 5/2001) at
https://grants.nih.gov/grants/funding/phs398/phs398.html includes step-
by-step guidance for preparing modular grants. Additional information
on modular grants is available at
https://grants.nih.gov/grants/funding/modular/modular.htm.
Applications requesting up to $250,000 per year in direct costs must be
submitted in a modular grant format. Applications requesting one
module ($25,000) above the cap due to subcontract or consortium
facilities and administrative costs associated with third party
agreements must also be submitted in modular format and may request up
to $275,000 per year in direct costs.
USING THE RFA LABEL: The RFA label available in the PHS 398 (rev.
5/2001) application form must be affixed to the bottom of the face page
of the application. Type the RFA number on the label. 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 2 of the face
page of the application form and the YES box must be marked. The RFA
label is also available at:
https://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten
original of the application, including the Checklist, and three signed,
photocopies, in one package to:
Center For Scientific Review
National Institutes Of Health
6701 Rockledge Drive, Room 1040, MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/courier service)
At the time of submission, two additional copies of the application and
all five collated sets of appendix material must be sent to Dr. Anne
Clark at the address listed under WHERE TO SEND INQUIRIES.
Please note that applications delivered by individuals are no longer
accepted; all applications must either come via courier delivery or the
United States Postal Service
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html).
APPLICATION PROCESSING: Applications must be received by the
application receipt date listed in the heading of this RFA. If an
application is received after that date, it will be returned to the
applicant without review.
The Center for Scientific Review (CSR) will not accept any application
in response to this RFA that is essentially the same as one currently
pending initial review, unless the applicant withdraws the pending
application. The CSR 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.
Principal investigators should not send supplementary material without
first contacting the Scientific Review Administrator (SRA). The SRA
will be identified in the letter sent to you indicating that your
application has been received. If you have not received such a letter
within three weeks after submitting the application, contact Dr. Anne
Clark at the address listed under WHERE TO SEND INQUIRIES.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR
and responsiveness by the (IC). Incomplete and/or non-responsive
applications will be returned to the applicant without further
consideration.
Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the (IC) in accordance with the review
criteria stated below. As part of the initial merit review, all
applications will:
o Receive a written critique
o 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 and assigned a priority score
o Receive a second level review by the NHLBI National Advisory Council.
REVIEW CRITERIA
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.
In the written comments, reviewers will be asked to discuss the
following aspects of your application in order to judge the likelihood
that the proposed research will have a substantial impact on the
pursuit of these goals:
o Significance
o Approach
o Innovation
o Investigator
o Environment
The scientific review group will address and consider each of these
criteria in assigning your application's overall score, weighting them
as appropriate for each application. Your application does not need to
be strong in all categories to be judged likely to have major
scientific impact and thus deserve a high priority score. For example,
you 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 your study address an important problem? If the
aims of your application are achieved, how do they advance scientific
knowledge? 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? Do you acknowledge potential problem areas and
consider alternative tactics?
(3) INNOVATION: Does your project employ novel concepts, approaches or
methods? Are the aims original and innovative? Does your project
challenge existing paradigms or develop new methodologies or
technologies?
(4) INVESTIGATOR: Are you appropriately trained and well suited to
carry out this work? Is the work proposed appropriate to your
experience level as the principal investigator and to that of other
researchers (if any)?
(5) ENVIRONMENT: Does the scientific environment in which your 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?
ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your
application will also be reviewed with respect to the following:
o PROTECTIONS: The adequacy of the proposed protection for animals, or
the environment, to the extent they may be adversely affected by the
project proposed in the application.
o DATA SHARING: The adequacy of the proposed plan to share tissue and
data.
o The capacity to show an optimal utilization of the resources (e.a. a
plan to utilize the same experimental animals and controls to answer
multiple biological questions and a plan for storage of tissue as
indicated in the Special Requirement section of this RFA).
BUDGET: The reasonableness of the proposed budget and the requested
period of support in relation to the proposed research.
RECEIPT AND REVIEW SCHEDULE
Letter of Intent Receipt Date: Feb 20 2003
Application Receipt Date: March 20 2003
Peer Review Date: June/July 2003
Council Review: September 4-5, 2003
Earliest Anticipated Start Date: September 30, 2003
AWARD CRITERIA
Award criteria that will be used to make award decisions include:
o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.
REQUIRED FEDERAL CITATIONS
PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT:
The Office of Management and Budget (OMB) Circular A-110 has been
revised to provide public access to research data through the Freedom
of Information Act (FOIA) under some circumstances. Data that are (1)
first produced in a project that is supported in whole or in part with
Federal funds and (2) cited publicly and officially by a Federal agency
in support of an action that has the force and effect of law (i.e., a
regulation) may be accessed through FOIA. It is important for
applicants to understand the basic scope of this amendment. NIH has
provided guidance at
https://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.
Applicants may wish to place data collected under this RFA in a public
archive, which can provide protections for the data and manage the
distribution for an indefinite period of time. If so, the application
should include a description of the archiving plan in the study design
and include information about this in the budget justification section
of the application. In addition, applicants should think about how to
structure informed consent statements and other human subjects
procedures given the potential for wider use of data collected under
this award.
URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and
proposals for NIH funding must be self-contained within specified page
limitations. Unless otherwise specified in an NIH solicitation,
Internet addresses (URLs) should not be used to provide information
necessary to the review because reviewers are under no obligation to
view the Internet sites Furthermore, we caution reviewers that their
anonymity may be compromised when they directly access an Internet
site.
HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to
achieving the health promotion and disease prevention objectives of
"Healthy People 2010," a PHS-led national activity for setting priority
areas. This RFA is related to one or more of the priority areas.
Potential applicants may obtain a copy of "Healthy People 2010" at
http://www.health.gov/healthypeople.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of
Federal Domestic Assistance No. 93.838 and is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review. Awards are made under authorization of
Sections 301 and 405 of the Public Health Service Act as amended (42
USC 241 and 284) and administered under NIH grants policies described
at https://grants.nih.gov/grants/policy/policy.htm and under Federal
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.
The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the 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.