RELEASE DATE:  April 1, 2004

PA NUMBER:  PA-04-080  

Expiration Date for R01 Non-AIDS Applications: November 2, 2006
Expiration Date for R01 AIDS and AIDS-Related Applications: January 3, 2007

January 3, 2007 - Effective with the February 5, 2007 submission date, 
all R01 applications must be submitted through using 
the electronic SF424 (R&R) application. Accordingly, this funding 
opportunity expires on January 3, 2007.  Unsolicited or 
investigator-initiated R01 electronic SF424 (R&R) applications may 
be submitted through the Research Project Grant (Parent R01) announcement.

Department of Health and Human Services (DHHS)

National Institutes of Health (NIH)

National Heart, Lung, and Blood Institute (NHLBI)


o Purpose of the PA
o Research Objectives
o Mechanism(s) of Support 
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements 
o Supplementary Instructions
o Where to Send Inquiries
o Submitting an Application
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations


The goal of this program announcement is to invite research applications to 
rapidly advance understanding of the pathogenesis of severe acute respiratory 
syndrome (SARS) in the lung using the following:

o  in vitro techniques (especially, using human viral isolates, human tissues 
and cells, and other biological samples) 
o  existing animal models of related coronavirus infections (e.g., porcine 
   respiratory CoV) 
o  non-human primate models of SARS
o  new ferret models of SARS
o  new rodent models of SARS
o  other appropriate animal models of SARS

The PA invites R01 applications for both high risk hypothesis generating 
research and hypothesis driven projects (if sufficient preliminary data are 
available), relevant to the pathogenesis of human lung disease caused by the 
human SARS coronavirus (SARS-CoV).


SARS, manifested by fever, pulmonary infiltrates, and often respiratory failure and 
death, infected more than 8000 people worldwide during the winter and spring of 2003.  
Overall, the death rate for SARS is estimated at 9.6%, but this rate is 50% or more 
for patients over 60 years of age.  The World Health Organization (WHO) and the 
Centers for Disease Control (CDC) quickly identified a new human coronavirus, SARS-
CoV, which appears to have “jumped” species from an animal reservoir, to infect humans 
and cause SARS.  At present, the outbreak has subsided, due to rigorous public health 
measures and probably to the seasonal nature of the coronavirus life cycle.  Questions 
about viral persistence in asymptomatic animal or human hosts or how SARS might emerge 
next remain unanswered for now.  The mechanism is not known.  It has been postulated 
that this might occur as a result of persistence and shedding of virus by asymptomatic 
human hosts or as a consequence of human contact with animals that are harboring the 
virus (possibly civet cats in China).  A few new cases have been reported from China 
in December 2003 and January 2004, but fortunately the disease does not appear to have 
spread.  At least some cases appear to have had contact with civet cats. 

Clinical and histopathological descriptions from Hong Kong, Toronto, Taiwan and 
elsewhere indicate that SARS causes severe pneumonia in a large proportion of infected 
individuals.  Many patients (19% of 196 studied in Toronto) develop an acute 
respiratory distress syndrome (ARDS), usually during the second week of illness.  The 
pulmonary histopathology of severe cases of SARS appears typical of ARDS.  Timing of 
the lung damage suggests that much of the injury may be mediated by the host immune 
system.  However, the extent to which lung injury results from SARS-CoV itself, by 
infection and replication in lung epithelial cells (and perhaps other cells), and the 
extent to which it is caused by the host immune responses to the virus are unclear.  
Co-existing infections (e.g., human paramyxovirus) are present in some specimens and 
may possibly play a role in triggering events leading to severe lung damage.   
Treatment with the wide spectrum antiviral drug ribavirin does not seem to be of any 
benefit.  Since it appears that the pathogenesis of lung disease in SARS may be 
largely due to an immune component, corticosteroids have been administered in an 
attempt to control this. The use of corticosteroids to reduce lung injury is currently 
controversial.  Other immune modulating agents (interferons) are being screened and 
considered for possible treatment studies, if there is a new outbreak of disease.  An 
issue for patients who survive SARS is the extent of residual lung damage and other 
sequellae.  Evidence of fibrosis, reported on lung biopsies and findings compatible 
with fibrosis on follow-up high resolution CT scans support the need to study this.

At this time, very little is known about the pathogenesis of SARS in the lung.  
Macaques have been infected in preliminary experiments and are reported to have lung 
lesions similar to those seen in humans.  Attempts to establish rodent models of lung 
disease have not succeeded yet, but infection can be established in rodents and models 
of other animal coronavirus diseases make it likely that a model may be established 
soon, either by direct infection or by modifying the SARS-CoV genome.  Recently, 
ferrets and domestic cats have been infected with SARS-CoV.  These animals can spread 
infection.  The ferrets become ill and die, not apparently from pneumonia, but the 
model is reproducible.

Meanwhile, much essential information about the pathogenesis of SARS in the lung could 
be gained from using established animal models of other coronaviruses and in vitro 
studies of SARS-CoV interactions with lung and immune cells.  

In addition to learning about how the virus infects lung cells, this PA specifically 
encourages in vitro research on the role of lung collectins and other extracellular 
lung host factors.  It encourages studies of endothelial and epithelial permeability, 
effects of SARS on fluid movements, and growth and differentiation of human lung cells 
(alveolar epithelial cells, fibroblasts, etc.).  Research on SARS-CoV interactions 
with human lung and immune cells and tissues is the primary focus, but research using 
engineered and related coronaviruses and animal cells pertinent to pathogenesis of 
SARS may also be responsive.  

This PA encourages pulmonary investigators to form collaborations to take full 
advantage of already established animal models of coronavirus infection and newly 
developed animal resources.  Of equal importance, pulmonary investigators are 
encouraged to use existing genetically altered mouse resources (e.g., the NHLBI 
Programs of Genomic Applications (PGA)) and if necessary to develop novel mice, 
engineered to incorporate or ablate components of immune function, to study the 
pathogenesis of SARS lung injury.  Collaborations with virologists to develop and 
study chimeric viruses are encouraged.  Chimeras might make it possible to use many 
existing mouse models and reagents that could quickly provide data on mechanisms of 
lung damage in SARS.  

Great care will be needed to protect personnel and prevent spread of viruses to other 
animals. Investigators will need to document that they have access to appropriate BSL3 
level facilities and that the investigators and other personnel are appropriately 

Research utilizing patient viral isolates, cells, tissue and other biological samples 
is encouraged if these are available.

It may also be possible to gain useful information by working with adapted strains of 
virus, e.g., a murine adapted strain or with existing animal models of related 
coronavirus diseases (pig, mouse, cat, etc.,) that may not require such stringent 

Examples of the type of research topics and approaches that would be solicited under 
this program announcement include (but are not limited to) the following: 

Determine which lung structural cells (e.g., epithelial, endothelial, etc.,)and immune 
and inflammatory cells support human SARS-CoV infection.
Study viral binding, receptors, co-receptors, replication, persistence, effects on 
host cell gene expression, and apoptosis.
Investigate immunological aspects of SARS-CoV infection, e.g., elaboration of 
cytokines, antigen presentation and effects of co-stimulation with other pathogens.
Address the role of immune responses, age related issues, surfactant proteins, and the 
effects of co-morbidities (e.g., underlying emphysema, diabetes) using animal models 
of SARS.

Elucidate pathogenesis by using animal models to study the effects of vaccines, 
antiviral drugs, and immune modulating agents that might moderate the manifestations 
of SARS in the lung.


This PA will use the NIH R01 award mechanism.  As an applicant, you will be solely 
responsible for planning, directing, and executing the proposed project.  

This PA uses just-in-time concepts.  It also uses the modular budgeting as well as the 
non-modular budgeting formats (see  Specifically, if you are 
submitting an application with direct costs in each year of $250,000 or less, use the 
modular budget format.  Otherwise, follow the instructions for non-modular budget 
research grant applications.  This program does not require cost sharing as defined in 
the current NIH Grants Policy Statement at  


You may submit (an) application(s) if your institution has any of the following 

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, hospitals, and 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign institutions/organizations
o Faith-based or community-based organizations


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 underrepresented racial and ethnic groups as well as 
individuals with disabilities are always encouraged to apply for NIH programs. 


Investigators working with SARS-CoV and other potentially dangerous infectious agents 
will need to document that they have access to carefully controlled BSL3 laboratories, 
properly isolated animal housing, and the availability of appropriately trained 
personnel. This program announcement requires that investigators who plan to work with 
SARS-CoV and other agents needing BSL3 facilities must demonstrate close coordination 
with groups that have BSL3 facilities and expertise.  
This is not intended as a vaccine or drug development program. Studies in which 
vaccines or drugs are used to elucidate the pathogenesis of SARS in the lung may be 
considered responsive to this PA. However, studies that focus on vaccine and drug 
development will not be considered responsive.

Work on normal lung tissue and cells may be used for comparison purposes, but to be 
responsive to the PA the proposed research projects must focus on the pathogenesis of 
SARS in the lung.

All applications submitted in response to this PA must include plans for sharing data 
and other resources. 

Grantee's Meetings

Upon initiation of the program, the NHLBI will sponsor meetings to encourage exchange 
of information among investigators who participate in this program announcement.  In 
their budgets, applicants should include funds for annual one-day grantees' meetings, 
most likely in Bethesda, Maryland.  Applicants should also include a statement in 
their applications indicating their willingness to participate in these meetings.  The 
first such meeting probably will take place about 12 months after the awards are 


We encourage your inquiries concerning this PA and welcome the opportunity to answer 
questions from potential applicants.  Inquiries may fall into two areas:  
scientific/research and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Hannah H. Peavy, M.D.
Division of Lung Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10018
Bethesda, MD  20892-7952
Phone:  (301) 435-0222
Fax:  (301) 480-3557

o Direct your questions about financial or grants management matters to:

Robert Pike
Grants Management Officer
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7144, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0171
FAX:  (301) 480-3310


Applications must be prepared using the PHS 398 research grant application 
instructions and forms (rev. 5/2001). Applications must have a Dun and Bradstreet 
(D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when 
applying for Federal grants or cooperative agreements. The DUNS number can be obtained 
by calling (866) 705-5711 or through the web site at 
The DUNS number 
should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 is 
available at n 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 710-0267, Email:

The title and number of this program announcement must be typed on line 2 
of the face page of the application form and the YES box must be checked. 

APPLICATION RECEIPT DATES: Applications submitted in response to this program 
announcement will be accepted at the standard application deadlines, which are 
available at  Application 
deadlines are also indicated in the PHS 398 application kit.

up to $250,000 per year in direct costs must be submitted in a modular budget grant 
format.  The modular budget 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 
includes step-by-step guidance for preparing modular grants.  Additional information 
on modular grants is available at

Applications requesting $500,000 or more in direct costs for any year must include a 
cover letter identifying the NIH staff member within one of NIH institutes or centers 
who has agreed to accept assignment of the application.   

Applicants requesting more than $500,000 must carry out the following steps:
1) Contact the IC program staff at least 6 weeks before submitting the application, 
i.e., as you are developing plans for the study; 

2) Obtain agreement from the IC staff that the IC will accept your application for 
consideration for award; and,
3) Identify, in a cover letter sent with the application, the staff member and IC who 
agreed to accept assignment of the application.  

This policy applies to all investigator-initiated new (type 1), competing continuation 
(type 2), competing supplement, or any amended or revised version of these grant 
application types. Additional information on this policy is available in the NIH Guide 
for Grants and Contracts, October 19, 2001 at: 

SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the 
application, including the checklist, and five 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)

APPLICATION PROCESSING: Applications must be mailed on or before the receipt dates 
described at  The CSR will not accept 
any application in response to this PA 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 a substantial revision of an 
unfunded version of an application already reviewed, but such application must include 
an Introduction addressing the previous critique.  

Although there is no immediate acknowledgement of the receipt of an 
application, applicants are generally notified of the review and funding assignment 
within 8 weeks.


Applications submitted for this PA will be assigned on the basis of established PHS 
referral guidelines.  Appropriate scientific review groups convened in accordance with 
the standard NIH peer review procedures ( will 
evaluate applications for scientific and technical merit.  

As part of the initial merit review, all applications will:

o Undergo a selection process in which only those applications deemed to have the 
highest scientific merit, generally the top half of applications under review, will be 
discussed and assigned a priority score
o Receive a written critique
o Receive a second level review by the appropriate national advisory council or board. 


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 evaluate application in order to judge the likelihood that 
the proposed research will have a substantial impact on the pursuit of these goals.  
The scientific review group will address and consider each of the following criteria 
in assigning the application’s overall score, weighting them as appropriate for each 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
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.

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?

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?

INNOVATION: Does the project employ novel concepts, approaches or methods? Are the 
aims original and innovative? Does the project challenge existing paradigms or develop 
new methodologies or technologies?

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)?

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?  

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items 
will be considered in the determination of scientific merit and the priority score: 
PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and 
protections from research risk relating to their participation in the proposed 
research will be assessed. (See criteria included in the section on Federal Citations, 
include subjects from both genders, all racial and ethnic groups (and subgroups), and 
children as appropriate for the scientific goals of the research will be assessed.  
Plans for the recruitment and retention of subjects will also be evaluated. (See 
Inclusion Criteria in the sections on Federal Citations, below).

CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used 
in the project, the five items described under Section f of the PHS 398 research grant 
application instructions (rev. 5/2001) will be assessed.  


Sharing Research Data 

Applicants requesting more than $500,000 in direct costs in any year of the 
proposed research are expected to include a data sharing plan in their 
application. The reasonableness of the data sharing plan or the rationale for 
not sharing research data will be assessed by the reviewers. However, reviewers 
will not factor the proposed data sharing plan into the determination of 
scientific merit or priority score.  
( )
BUDGET:  The reasonableness of the proposed budget and the requested period of support 
in relation to the proposed research.


Applications submitted in response to a PA will compete for available funds with all 
other recommended applications.  The following will be considered in making funding 

o Scientific merit of the proposed project as determined by peer review
o Availability of funds 
o Relevance to program priorities


HUMAN SUBJECTS PROTECTION:  Federal regulations (45CFR46) require that applications 
and proposals involving human subjects must be evaluated with reference to the risks 
to the subjects, the adequacy of protection against these risks, the potential 
benefits of the research to the subjects and others, and the importance of the 
knowledge gained or to be gained.

DATA AND SAFETY MONITORING PLAN: Data and safety monitoring is required for all types 
of clinical trials, including physiologic, toxicity, and dose-finding studies (phase 
I); efficacy studies (phase II), efficacy, effectiveness and comparative trials (phase 
III). The establishment of data and safety monitoring boards (DSMBs) is required for 
multi-site clinical trials involving interventions that entail potential risk to the 
participants.(NIH Policy for Data and Safety Monitoring, NIH Guide for Grants and 
Contracts, June 12, 1998:  

SHARING RESEARCH DATA:  Starting with the October 1, 2003 receipt date, 
investigators submitting an NIH application seeking $500,000 or more in direct costs 
in any single year are expected to include a plan for data sharing or state why this 
is not possible. . Investigators should seek guidance 
from their institutions, on issues related to institutional policies, local IRB rules, 
as well as local, state and Federal laws and regulations, including the Privacy Rule. 
Reviewers will consider the data sharing plan but will not factor the plan into the 
determination of the scientific merit or the priority score.

that women and members of minority groups and their sub-populations must be included 
in all NIH-supported clinical research projects unless a clear and compelling 
justification is 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 clinical research should read the "NIH Guidelines for 
Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 
2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 
(; a complete copy 
of the updated Guidelines are available at  The 
amended policy incorporates: the use of an NIH definition of clinical research; 
updated racial and ethnic categories in compliance with the new OMB standards; 
clarification of language governing NIH-defined Phase III clinical trials consistent 
with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the 
extramural community.  The policy continues to require for all NIH-defined Phase III 
clinical trials that: a) all applications or proposals and/or protocols must 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) 
investigators must report annual accrual and progress in conducting analyses, as 
appropriate, by sex/gender and/or racial/ethnic group differences.

The NIH maintains a policy 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 (Type1) 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 is available at 

requires education on the protection of human subject participants for all 
investigators submitting NIH proposals for research involving human subjects.  You 
will find this policy announcement in the NIH Guide for Grants and Contracts 
Announcement, dated June 5, 2000, at

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs 
can be found at and at  Only research 
using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry 
will be eligible for Federal funding (see   
It is the responsibility of the applicant to provide, in the project description and 
elsewhere in the application as appropriate, the official NIH identifier(s)for the 
hESC line(s)to be used in the proposed research.  Applications that do not provide 
this information will be returned without review. 

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

Applicants may wish to place data collected under this PA 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.

of Health and Human Services (DHHS) issued final modification to the “Standards for 
Privacy of Individually Identifiable Health Information”, the “Privacy Rule,” on 
August 14, 2002.  The Privacy Rule is a federal regulation under the Health Insurance 
Portability and Accountability Act (HIPAA) of 1996 that governs the protection of 
individually identifiable health information, and is administered and enforced by the 
DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule 
(classified under the Rule as “covered entities”) must do so by April 14, 2003  (with 
the exception of small health plans, which have an extra year to comply).  

Decisions about applicability and implementation of the Privacy Rule reside with the 
researcher and his/her institution. The OCR website 
( provides information on the Privacy Rule, including a 
complete Regulation Text and a set of decision tools on “Am I a covered entity?”  
Information on the impact of the HIPAA Privacy Rule on NIH processes involving the 
review, funding, and progress monitoring of grants, cooperative agreements, and 
research contracts can be found at

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 

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance at  and is not subject to the 
intergovernmental review requirements of Executive Order 12372 or Health Systems 
Agency review.  Awards are made under the authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284 and under Federal Regulations 
42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and 
conditions, cost principles, and other considerations described in the NIH Grants 
Policy Statement.  The NIH Grants Policy Statement can be found at 

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.

Weekly TOC for this Announcement
NIH Funding Opportunities and Notices

Office of Extramural Research (OER) - Home Page Office of Extramural
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