ROLE OF INFECTIOUS AGENTS IN VASCULAR DISEASES
Release Date: September 10, 2001
RFA: RFA-HL-02-002
National Heart, Lung, and Blood Institute
(http://www.nhlbi.nih.gov)
Letter of Intent Receipt Date: January 7, 2002
Application Receipt Date: February 12, 2002
THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR
INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS REQUESTING LESS THAN
$250,000 PER YEAR IN ALL YEARS. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN
SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT
https://grants.nih.gov/grants/funding/phs398/phs398.html.
PURPOSE
The National Heart, Lung, and Blood Institute (NHLBI) invites research grant
applications to conduct studies on the role of infectious agents in the
development of vascular disease. A potentially important role of infectious
agents in the development of vascular disease is suggested by studies showing
an association between vascular diseases and certain bacterial and viral
infections. The objective of this program is to encourage in vitro and in
vivo research on the specific cellular and molecular mechanisms by which
infectious agents contribute to atherogenesis. The secondary objective is to
encourage the development of the biological basis for therapeutic
interventions that target these molecular mechanisms.
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 Request for Applications (RFA),
"Role of Infectious Agents in Vascular Diseases" 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/.
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. Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as Principal
Investigators.
MECHANISM OF SUPPORT
This RFA will use the National Institutes of Health (NIH) investigator-
initiated grant award (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 an application submitted in response
to this RFA may not exceed four years. This RFA is a one-time solicitation.
Future unsolicited competing continuation applications will compete with all
investigator-initiated applications and be reviewed according to the customary
peer review procedures. The anticipated award date is September 30, 2002.
Specific application instructions have been modified to reflect "MODULAR
GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the
NIH. Complete and detailed instructions and information on Modular Grant
applications have been incorporated into the PHS 398 (rev. 5/2001).
Additional information on Modular Grants can be found at
https://grants.nih.gov/grants/funding/modular/modular.htm
FUNDS AVAILABLE
The NHLBI intends to commit approximately $3 million in FY 2002 to fund up to
eight new grants in response to this RFA. An applicant may request a project
period of up to four years and a budget for direct costs not to exceed
$250,000 per year, or ten modules of $25,000 per year. Because the nature and
scope of the research proposed may vary, it is anticipated that the size 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.
RESEARCH OBJECTIVES
Background
Established cardiovascular risk factors such as hypercholesterolemia, smoking,
diabetes, and hypertension do not fully explain the etiology or incidence of
coronary heart disease. Such findings suggest that additional, less
substantiated risk factors may contribute significantly to vascular
pathogenesis. For a number of years, observational studies in humans have
provided intriguing hints linking certain viral and bacterial infections to
atherosclerosis, coronary events, or restenosis after arterial intervention.
The in vivo documentation of the involvement of members of the herpes virus
family in atherosclerotic processes ranges from solid evidence of causality in
chickens to observational and associative studies in humans. More recently, a
growing body of in vitro work has suggested possible pathophysiological
mechanisms by which herpes viruses, most notably cytomegalovirus (CMV), might
contribute to vascular disease. Regarding bacterial agents, the association
of Chlamydia pneumoniae and atherosclerosis has been demonstrated indirectly
by seroepidemiology, and this obligate intracellular prokaryote has been
detected in atherosclerotic plaques. In studies performed in vitro,
atherogenic changes in vascular cells following infection by Chlamydia have
been described. Recent studies combining animal models of atherosclerosis
with animal models of infectious disease have produced results consistent with
a vasculopathic role for infectious agents in mammals.
Both Chlamydia and CMV are ubiquitous pathogens found in 50 to 70% of most
populations where they can reside intracellularly in a chronic, persistent or
latent state. Whether periods of reactivation and productive infection are
required for pathogenesis is unknown. Although Chlamydia and CMV have been
found in vascular lesions, the primary cell types in which these agents act is
still unclear. Macrophages are thought to be one of the primary sites of CMV
latency, and macrophage infiltration of injured vascular wall endothelium may
be the method by which CMV is deposited in plaques. However, the conditions
and specific factors controlling macrophage permissiveness for CMV,
establishment of CMV latency, and reactivation of productive infection are not
well understood. Similarly, the local factors and conditions that mediate the
ability of CMV to infect vascular endothelium or smooth muscle cells are
largely unknown. It has been hypothesized that Chlamydia antigens found in
plaques may have been deposited by circulating macrophages carrying
phagocytized or parasitic Chlamydia from the lung.
A number of in vitro studies in macrophages, endothelial cells, and smooth
muscle cells have identified mechanisms by which Chlamydia, CMV or other
herpes viruses might potentiate atherogenesis. Such mechanisms include
increases in proliferation, procoagulant proteins, leukocyte adhesion, and
cytokine production, as well as augmented cholesterol uptake and
esterification. CMV immediate-early gene products inhibit the tumor
suppressor p53, which may mediate the accumulation of smooth muscle cells seen
in atherosclerotic plaques. DNA fragments from herpes simplex virus (HSV),
and CMV have been shown to immortalize aortic smooth muscle cells. Chlamydia
and herpes virus infection of endothelium each result in increased expression
of growth factors, cytokines, and cell adhesion molecules, which promotes
binding of inflammatory cells--a cascade that may be accompanied by
endothelial dysfunction. Chlamydia, HSV or CMV infection of endothelial cells
also increases acute phase reactants, and each of these pathogens alters
cholesterol metabolism in infected cells. For many of these infection-related
cellular changes, a cause-and-effect relationship remains to be proven
definitively by the identification of the specific molecular interactions that
trigger these events.
Mechanistic studies suggest that gene products of infectious agents can act
directly on vascular cells. Nevertheless, an important question is whether
infectious agents--only sometimes found in atheroma--can exert vasculopathic
effects without infecting vascular cells. For example, the atherogenic
changes seen in infected endothelial and smooth muscle cells can be caused by
systemic inflammation due to chronic infection and activation of circulating
inflammatory cells. In addition, another important mechanism by which
infectious agents might increase vascular disease without directly infecting
vascular cells is through exacerbation or augmentation of well known risk
factors such as hypercholesterolemia.
Several animal models have been developed for vascular diseases, including
atherosclerosis, in non-human primates, rabbits and mice. CMV infection has
been studied in numerous animals including rats, mice and guinea pigs, and
Chlamydia infection has been studied in rabbits and mice. More recent studies
combining infectious-agent and atherosclerotic animal models have shown
increases in various measures of vascular disease such as prevalence of
arterial inflammatory cell infiltrates or accelerated arterial intimal
thickening. While the development of these models is essential, it is
critical that animal models be established that mimic the subclinical status
of these pathogens in man.
The establishment of infectious disease/vascular disease animal models opens
the opportunity to test specific inhibitors of the disease process, which can
provide solid evidence of causality. Also, these models allow rational
development of antiviral and antibacterial therapies including drugs,
vaccines, and other novel approaches that target specific pathogenic
mechanisms. A preventive CMV vaccine has been available for a number of years
but it has limited efficacy and is unlikely to affect latent CMV. A Chlamydia
vaccine is not yet available. While traditional vaccines may be beneficial
for uninfected individuals, they may be ineffective against existing
intracellular latent and chronic pathogens. Therefore, the testing of a
variety of therapeutic possibilities that target direct, indirect, or systemic
atherogenic mechanisms of infectious agents seems warranted.
It is possible that infectious agents currently showing weak associations with
vascular disease, as well as infectious agents not previously associated with
atherogenesis, may contribute to vascular pathogenesis. Indeed, the presence
of such unrecognized agents could be a confounding factor in studies of
infectious agents that are associated with increased vascular disease.
Therefore, studies of new agents and those that have been shown to have
marginal association to vascular disease will continue to be important.
Research Areas
Areas of research that would be considered responsive to the RFA are listed
below. These areas are not inclusive, however, and investigators are strongly
encouraged to discuss proposed submissions with the appropriate staff at the
NHLBI.
o Biology of Latency and Infection:
Identification and study of in vivo sites of latency at the organ, tissue, and
cellular levels, characterization of conditions/factors controlling
permissiveness for infection, establishment of latency, and reactivation of
productive infection in macrophages, endothelium, smooth muscle cells, and
other relevant cell types.
o Molecular Mechanisms of Pathogenesis:
Characterization of direct, specific molecular interactions between
genomes/gene products of infectious agents and infected cells, and the
resulting atherogenic potential of altered cell characteristics and functions,
study of indirect or systemic effects of infectious agents harbored in both
vascular and non-vascular-wall cells, such as macrophages, and other cell
types, studies of specific mechanisms by which infectious agents might augment
or exacerbate traditional risk factor such as hypercholesterolemia,
hypertension and others.
o Animal Models:
Development and characterization of models of atherosclerosis in which the
infectious agent is the primary cause of atherosclerosis. Specific aims
should include studies elucidating the underlying mechanisms. In addition,
plans to disseminate the animal models and willingness to share these models
and tissue from the models with the scientific community are expected to be
part of these proposals.
o Animal Studies:
Studies in animal models of infection and atherosclerosis that define the
status of the infectious agent including pathogen load, temporal and spatial
distribution, and state of latency/activation with the aim of precisely
determining and substantiating in vivo pathobiologic mechanisms of
atherogenesis. These studies may be done either in existing models or in
models developed specifically for this purpose.
o Molecular Interventions:
Development of specific interventions in both in vitro and in vivo systems
that target the molecular mechanisms of atherogenesis induced by infectious
agents in order to establish causality, and determine possible therapeutic
approaches.
o Other Pathogens:
Study of vasculopathic effects of agents with potential association with
atherogenesis.
EXCLUSIONS
Applications focusing on the following areas will be considered nonresponsive
to the objectives of this initiative:
o Applications that propose development of animal models without plans to
study the underlying molecular mechanisms, and prevention or treatment
modalities.
o Applications that propose to study the biology of latency of infection not
related to atherogenesis.
o Applications that propose to study the role of HIV in atherogenesis.
o Applications that propose large clinical or epidemiological studies.
SPECIAL REQUIREMENTS
Upon initiation of the program, NHLBI will sponsor periodic meetings to
encourage exchange of information and collaborations among investigators who
participate in this program. Applicants should request travel funds for the
Principal Investigator and key personnel for two 2-day meetings, to be held
the first and the third year of the program, most likely in Bethesda,
Maryland. Applicants should include a statement in their applications
indicating their willingness to participate in these meetings, and to interact
openly and to share animal models, tissues and special reagents with other
study participants to provide the greatest promise for scientific advances
from the approved research scope of the awards.
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 sub-populations 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 indicating that inclusion
is inappropriate with respect to the health of the subjects or 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
UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research," published in the NIH Guide for Grants and Contracts on
August 2, 2000
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html),
a complete copy of the updated Guidelines are available at
https://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The
revisions relate to NIH defined Phase III clinical trials and require: a) all
applications or proposals and/or protocols to provide a description of plans
to conduct analyses, as appropriate, to address differences by sex/gender
and/or racial/ethnic groups, including subgroups if applicable, and b) all
investigators to report accrual, and to conduct and report analyses, as
appropriate, by sex/gender and/or racial/ethnic group differences.
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them.
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.
All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines" on the Inclusion of Children as Participants in
Research Involving Human Subjects that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html
Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES. Program staff may also provide additional relevant
information concerning the policy.
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS
NIH policy requires education on the protection of human subject participants
for all investigators submitting NIH proposals for research involving human
subjects. This policy announcement is found in the NIH Guide for Grants and
Contracts Announcement dated June 5, 2000, at the following website:
https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.
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. Reviewers are cautioned that their anonymity may
be compromised when they directly access an Internet site.
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.
LETTER OF INTENT
Prospective applicants are asked to submit 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
a subsequent application, the information that it contains allows NHLBI staff
to estimate the potential review workload and plan the review.
The letter of intent is to be sent to Dr. Deborah Beebe at the address listed
under INQUIRIES by January 7, 2002.
APPLICATION PROCEDURES
The PHS 398 research grant application instructions and forms (rev. 5/2001) at
https://grants.nih.gov/grants/funding/phs398/phs398.html are to be used in
applying for these grants. This version of the PHS 398 is available in an
interactive, searchable PDF format. Beginning January 10, 2002, the NIH will
return applications that are not submitted on the 5/2001 version. For further
assistance contact GrantsInfo, Telephone 301/710-0267, Email:
GrantsInfo@nih.gov.
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS
The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets. Only
limited budgetary information is required under this approach. The just-in-
time concept allows applicants to submit certain information only when there
is a possibility for an award. It is anticipated that these changes will
reduce the administrative burden for the applicants, reviewers and NIH staff.
The research grant application form PHS 398 (rev. 5/2001) at
https://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in
applying for these grants, with modular budget instructions beginning on page
13 of the application instructions.
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.
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 as well as
all five collated sets of Appendix material must be sent to Dr. Deborah Beebe
at the address listed under Inquiries. 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.
Principal investigators should not sent 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 yet received such a letter within three weeks after
submitting the application, contact Dr. Deborah Beebe at the address listed
under Inquiries.
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.
REVIEW CONSIDERATIONS
Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NHLBI. 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 NHLBI in accordance with the review criteria stated below. 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 National Heart, Lung and, Blood 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 the application 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 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 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?
In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:
o The adequacy of plans to include both genders, minorities and their
subgroups, and children as appropriate for the scientific goals of the
research. Plans for the recruitment and retention of subjects will also be
evaluated.
o The reasonableness of the proposed budget and duration in relation to the
proposed research.
o The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project
proposed in the application.
o The adequacy of the proposed plan to share and disseminate data, animal
models (newly developed and existing), tissues and special reagents.
Schedule
Letter of Intent Receipt Date: January 7, 2002
Application Receipt Date: February 12, 2002
Peer Review Date: May-June, 2002
Council Review: September 5-6, 2002
Earliest Anticipated Start Date: September 30, 2002
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.
INQUIRIES
Inquiries concerning this RFA are encouraged. The opportunity to clarify any
issues or answer questions from potential applicants is welcome.
Direct inquiries regarding programmatic issues to:
Eser Tolunay, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Dr., Room 10-186, MSC 7956
Bethesda, MD 20892
Telephone: (301) 435-0550
FAX: (301) 480-2858
Email: TolunayE@nhlbi.nih.gov
Send letter of intent and 2 copies of the application, and direct inquiries
regarding review matters to:
Deborah P. Beebe, Ph. D.
Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Dr., Room 7178, MSC 7924
Bethesda, MD 20892-7924
Telephone: (301) 435-0270
Fax: (301) 480-3541
Email: BeebeD@nhlbi.nih.gov
Direct inquiries regarding fiscal matters to:
Owen Bobbitt
Grants Operations Branch
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Dr., Room 7134, MSC 7926
Bethesda, MD 20892
Telephone: (301) 435-0177
FAX: (301) 480-0422
Email: BobbittO@nhlbi.nih.gov
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance No.
93.837. 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 and Federal Regulations 42 CFR 52 and 45 CFR Parts
74 and 92. 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 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.