EVOLUTIONARY MECHANISMS IN INFECTIOUS DISEASE

RELEASE DATE:

PA NUMBER:  PA-02-113 (This PA has been reissued, see PA-05-079)

EXPIRATION DATE:   March 29, 2005

National Institute of General Medical Sciences
 (http://www.nigms.nih.gov/)

National Institute of Diabetes and Digestive and Kidney Diseases
 (http://www.niddk.nih.gov/)

THIS PA CONTAINS THE FOLLOWING INFORMATION

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

PURPOSE

The goal of the announcement is to encourage development of a predictive 
science of infectious disease by applying the perspectives, theories, and 
methods from relevant scientific disciplines to important issues of disease 
emergence, prevention, and the consequences of treatment.  Research projects 
involving interdisciplinary collaborations are an explicit goal of this 
announcement.  Approaches might include, but are not limited to, evolutionary 
biology, microbiology, population dynamics, chemistry, biochemistry, and 
computational biology.  The focus is limited to discovery of fundamental 
biological principles rather than to detailed knowledge or treatment of 
specific diseases. 

RESEARCH OBJECTIVES

Background

A predictive science of infectious disease depends on our ability to 
anticipate with some confidence the behavior of host/parasite systems.  
Predictions might include when and where new infectious diseases will emerge, 
under what conditions drug resistance will arise, the consequences of 
therapeutic interventions, and the impact of ecological changes.  

The rise of infectious systems consisting of parasite(s), vector(s), and 
host(s) are subject to dynamic interactions at many levels from the chemical 
to the populational.  For example, the ability of an infectious species to 
colonize plant or animal hosts, to proliferate, to cause disease, and to 
spread depends on a variety of factors, such as its genetic characteristics, 
its life history, and its mode of transmission, all of which are subject to 
evolutionary change.  The ability of a host species to prevent, control, 
and/or promote interactions similarly depends on its innate defense system 
(including immune defenses), its behavior, its environment, and human 
intervention.  Population dynamics, including population density, migration, 
population subdivision, and competition for resources, affect the evolution 
of pathogens, vectors, and hosts.

Evolutionary biology, molecular biology, genetics, systematics, chemistry, 
biochemistry, mathematics, and other disciplines, will contribute 
significantly to the development of a predictive science of infectious 
systems.  For example, identifying the origins and host ranges of infectious 
agents requires a variety of molecular, genetic, mathematical, and 
evolutionary tools.  Intervention to prevent or treat infections by behavior 
modification, control of vectors, vaccination, drug therapy or other means 
influences a variety of dynamic evolutionary processes in individual hosts, 
communities of hosts, and communities of pathogenic organisms.  Understanding 
the conditions under which interventions fail (e.g., antibiotic resistance or 
reversion of live vaccines to virulence) and designing protocols to prevent 
these failures requires application of evolutionary understanding.  
Multidisciplinary approaches are essential for anticipating the conditions 
under which new infectious diseases will emerge and old ones will re- emerge.

While there is widespread interest in understanding, preventing, and treating 
infectious diseases and anticipating their emergence and re-emergence, 
research into evolutionary aspects of infectious systems has been limited.  
With a few exceptions, broad interdisciplinary approaches are rarely employed 
in infectious disease research or in the design of protocols to prevent and 
treat infections.  The goal of this initiative is to remedy this situation by 
supporting collaborations among scientists with diverse areas of expertise.

Scientific Objectives

Proposals for research projects responsive to this announcement should 
address broad evolutionary questions that are relevant to infectious disease 
in general.  Because host/parasite and other symbiotic systems exhibit a 
continuum of behavior, ranging from beneficial to pathological associations, 
general evolutionary principles can be expected to emerge from studies using 
a variety of models.  For this reason, a variety of model systems, including 
plant and microbial systems will also be considered when they are used to 
address fundamental mechanisms of evolution.  Human studies are included when 
the goal of the research is basic knowledge of the evolution of infectious 
systems rather than of a specific disease entity.  Studies that combine 
quantitative, theoretical, and experimental approaches are especially 
encouraged.  Applicants must clearly explain how the proposed approaches and 
perspectives are expected to contribute to development of a predictive 
science of infectious disease.

Within the areas of investigation described below, relevant applications 
could focus on, but are not limited to, one or more of the following aspects:

1. Causes and sources of infectious disease.
o Genetic variation and structure of pathogen populations and the genetic 
relationships between commensal and pathogenic members of closely related 
taxa
o Population analyses of the contributions and sources of the vertical and 
horizontal transfer of genes and accessory elements coding for virulence 
determinants, host range and specificity, and drug resistance
o Genetic factors (pathogen, host, or vector) responsible for geographic and 
temporal variation in disease frequency and severity

2. Interactions between hosts and pathogens.
o Contribution of population dynamic and evolutionary processes to the 
pathogenesis and virulence of infecting organisms
o Establishment of model systems to explore the relationship between the 
evolution of pathogenic organisms and factors affecting host susceptibility, 
including ecological, social, and other environmental factors
o Mechanisms of chemical signaling and communication

3. Consequences of intervention strategies.
o Within-host population dynamics related to intervention strategies, 
including reversion to virulence of live vaccines (as opposed to outgrowth of 
existing unattenuated organisms), as well as evolution of resistance 
following antimicrobial drug therapy or vaccination
o Establishment of model systems (either in vitro systems, or in vivo systems 
involving non-human pathogens and/or animal, microbe, or plant hosts) to 
predict the ecological and evolutionary consequences of programs involving 
host behavior, vaccination, antimicrobial drug therapy, and other 
intervention strategies on pathogen, host, and vector populations
o Novel mechanisms of antibiotic action
o Use of evolutionary approaches to create new strategies for drug 
development and delivery
o Identification of new resistance mechanisms, including how they arose 

4. Establishment of model systems to explore the environmental, physiological 
and genetic factors responsible for generating and maintaining variation in 
pathogen, vector, and host populations, including co-evolutionary dynamics.

5. Natural history of pathogenic organisms.
o Evolutionary basis for the normal range of pathogen habitats and hosts
o Establishment of model systems to explore the molecular basis of host 
barriers that must be overcome by pathogens in order to extend their ranges
o Establishment of model systems to explore the molecular, individual, and 
population dynamics of extending the niche or host range of a pathogen.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) research project 
grant (R01).  As an applicant, you will be solely responsible for planning, 
directing, and executing the proposed project.  Supplements to existing NIH 
grants will also be considered. The total project period for an application 
submitted in response to this PA may not exceed five years.

This PA uses just-in-time concepts.  It also uses the modular as well as the 
non-modular budgeting formats (see 
http://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.

ELIGIBILITY REQUIREMENTS

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 institutions

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

WHERE TO SEND INQUIRIES

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:

Dr. Irene Anne Eckstrand
Division of Genetics and Developmental Biology
National Institute of General Medical Sciences
Building 45 Center Drive, Room MSC 6200
Bethesda, MD  20892
Telephone:  (301) 594-0943
FAX:  (301) 480-2228
Email: Irene_Eckstrand@nih.gov

Frank A. Hamilton, M.D., MPH
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd., Democracy 2, Room 669
Bethesda, Maryland 20892-5450
Telephone: (301) 594-8877
FAX :  (301) 480-8300
Email: fh14e@nih.gov

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

Ms. Marcia Cohn
Grants Management Office
National Institute of General Medical Sciences
Building 45 Center Drive, Room MSC 6200
Bethesda, MD  20892
Telephone:  (301) 594-3918
FAX:  (301) 480-1969
Email: cohnm@nigms.nih.gov

Ms. Carolyn Kofa
Grants Management Branch
Division of Extramural Activities
National Institutes of Diabetes and Digestive and Kidney Diseases
6707 Democracy Blvd. 2 Democracy Plaza, Room 727
Bethesda, Maryland 20892
Telephone:  (301) 594-6787
FAX:  (301) 480-3604
Email: kofac@extra.niddk.nih.gov

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 
http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive 
format.  For further assistance contact GrantsInfo, Telephone (301) 435-0714, 
Email: GrantsInfo@nih.gov.

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

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 
http://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 
http://grants.nih.gov/grants/funding/modular/modular.htm.

SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: 
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 http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. 

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 received by or mailed on or 
before the receipt dates described at 
http://grants.nih.gov/grants/funding/submissionschedule.htm.  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 application already reviewed, but 
such application must include an Introduction addressing the previous 
critique.

PEER REVIEW PROCESS

Applications submitted for this PA will be assigned on the basis of 
established PHS referral guidelines.  An appropriate scientific review group 
convened in accordance with the standard NIH peer review procedures 
(http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific 
and technical merit.  

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

o Receive a written critique
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 second level review by the appropriate national advisory council 
or board

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:

PROTECTIONS:  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.

INCLUSION:  The adequacy of plans to include subjects from both genders, all 
racial and ethnic groups (and subgroups), and children as appropriate for the 
scientific goals of the research.  Plans for the recruitment and retention of 
subjects will also be evaluated. (See Inclusion Criteria included in the 
section on Federal Citations, below)

DATA SHARING:  The adequacy of the proposed plan to share data. 

BUDGET:  The reasonableness of the proposed budget and the requested period 
of support in relation to the proposed research.

AWARD CRITERIA

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 decisions:  

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

REQUIRED FEDERAL CITATIONS 

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 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 AMENDMENT "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 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html), 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm
.  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.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS:  
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 (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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm. 

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.  You will find this policy announcement in the NIH Guide for Grants 
and Contracts Announcement, dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on 
hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at  
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  Only 
research using hESC lines that are registered in the NIH Human Embryonic Stem 
Cell Registry will be eligible for Federal funding (see http://escr.nih.gov).   
It is the responsibility of the applicant to provide 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. 

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 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

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.

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 PA 
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. 93.862, 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 
http://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.


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NIH Funding Opportunities and Notices


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