LEIOMYOMATA UTERI: BASIC SCIENCE AND TRANSLATIONAL RESEARCH
RELEASE DATE: November 18, 2002
RFA: HD-03-005
National Institute of Child Health and Human Development (NICHD)
(http://www.nichd.nih.gov/)
National Institute of Environmental Health Sciences (NIEHS)
(http://www.niehs.nih.gov/)
Office of Research on Women's Health (ORWH)
(http://www4.od.nih.gov/orwh/)
LETTER OF INTENT RECEIPT DATE: March 14, 2003
APPLICATION RECEIPT DATE: April 14, 2003
THIS RFA CONTAINS THE FOLLOWING INFORMATION
o Purpose of this RFA
o Research Objectives
o Mechanism 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 Institute of Child Health and Human Development (NICHD), the
National Institute of Environmental Health Sciences (NIEHS), and the NIH
Office of Research on Women's Health (ORWH) invite new and experienced
investigators to submit research grant applications in basic science,
environmental health science, and translational research with the goal of
translating advances in our understanding of the molecular basis of
leiomyomata uteri (uterine fibroids) into new therapies for prevention,
treatment, and cure of this common benign gynecologic disorder. This
solicitation focuses on basic science and translational research studies that
are innovative in their approach to determine the complex molecular basis of
this disorder. Results from this research are expected to have important
applications for moving advances in basic science research from the
laboratory to clinical practice.
RESEARCH OBJECTIVES
Background
This initiative addresses the need to increase our knowledge and
understanding about leiomyomata uteri and the biological processes that lead
to their development and long-term sequelae. The objective is to strengthen
research in this critical area of women's health, contribute to reducing the
burden of this disease, and improve the quality of life for women affected
with this disorder. Uterine leiomyomata constitute a significant public
health concern. While uterine leiomyomata represent the most common
gynecologic tumor in women, the mechanisms that initiate uterine leiomyoma
growth and pathogenesis are not completely understood. Several studies
estimate that 20 to 40 percent of reproductive age women have uterine
leiomyomata and, according to some reports, they are diagnosed in African
American women two to three times more frequently than in Caucasian women.
This disorder is clinically important because it is a significant source of
abnormal uterine bleeding, anemia, and pelvic pain. In addition to pain,
uterine leiomyomata may press on adjacent structures, leading to difficulty
with urination or defecation or dyspareunia. These symptoms frequently lead
to various medical and/or surgical interventions. Surgical procedures are of
primary concern, because uterine leiomyomata remain the leading indication
for a hysterectomy in the United States. Thus, both the economic costs and
effect on quality of life can be substantial. Increased emphasis on a
condition that poses a serious reproductive threat for many women and
represents a disproportionate burden for African American women can enhance
our ability to preserve the fertility and reproductive health of all women.
To address the need for increased attention in this area, NICHD collaborated
with the ORWH in sponsoring a workshop in 1992 on "Abnormal Uterine Bleeding,
Myomas and Infertility." At the workshop, experts defined and prioritized
research needs. The presentations and discussions stimulated the development
of ideas for new projects and, because of this meeting, the research
community was made aware of the interest of NICHD in these areas. This
workshop was followed by a Request for Applications on the Pathophysiology of
Endometriosis and Leiomyomata Uteri (RFA-HD-93-04), resulting in the award of
several new grants. In a subsequent workshop, convened in 1994, on
"Alternatives to Hysterectomy--Bench to Bedside," funded investigators, along
with outside experts, were brought together to discuss how evolving basic
science could now provide a framework for more applied or clinical research.
Topics included medical regimens, such as utilization of gonadotropin-
releasing hormone (GnRH) analogs, antiprogestins, prostaglandin inhibitors,
and conservative surgical approaches. This meeting demonstrated that while
researchers have gained some insight into the mechanisms that mediate uterine
leiomyoma development and growth, and some progress has been made, many
challenges remain. On October 7-8, 1999, the NICHD in collaboration with
NIEHS, ORWH, and the Public Health Service, Office of Women's Health,
convened another conference, entitled "Women's Health and the Environment:
The Next Century--Advances in Uterine Leiomyoma Research," to explore the
state-of-the-science. The distinguished panel of speakers provided a review
of the current approaches to the pathophysiology, mechanisms of tumor
development, epidemiology, environmental influences, and clinical
therapeutics related to uterine leiomyomata. A summary of the conference was
published in Environmental Health Perspectives, 2000, 108 (S5) 769-773. In
response to recommendations made at the conclusion of this conference,
priority was placed on stimulating relevant research strategies focusing on
promising and innovative studies that would continue to enhance our knowledge
of uterine leiomyomata. These activities have formed the groundwork for
assessing future research opportunities and complementing the ongoing
commitment of NICHD, NIEHS, and ORWH to support research important to women's
reproductive health.
Research Scope
The general scope of proposed studies could encompass determining the
etiology, diagnostic criteria, and underlying pathophysiology deemed
important for building a substantive knowledge base. Critical variables for
uterine leiomyoma growth, such as hormonal stimulation, molecular and
cytogenetic changes, differences in cell regulation, and the influence of
exposures to environmental agents are areas for further assessment.
Moreover, aspects of research such as preclinical studies, animal models,
basic biological processes, genetic factors, and translational research are
all potential avenues for further examination. This initiative is expected
to increase our knowledge about the underlying mechanisms that will build a
framework for strengthening the science base, improving clinical
applications, and providing clues for more effective conservative management
of this clinically relevant disorder.
Examples of the scope of research topics considered responsive to this
announcement include, but are not limited to, the following:
o Initiation of a genome-wide screen to characterize the genetic liability
for developing uterine leiomyomata, with particular emphasis on racial
overexpression in African American women, twin-pair correlation, and familial
predisposition;
o Elucidation of the role of genetic alterations in the process of tumor
transformation, correlating the cytogenetic and/or genomic abnormalities with
phenotypic expression;
o Development of surrogate animal models to assess the mechanism of leiomyoma
formation and to screen for candidate therapeutic agents and prevention
strategies;
o Identification of the basic molecular and cellular processes and
examination of the mechanisms by which estrogen and progesterone induce cell
transformation and promote tumor growth or suppression. Clarification of the
interaction between estrogen and progesterone and related growth factors;
o Study of the potential role of selective estrogen receptor modulators
(SERMs) on uterine leiomyoma development and growth. Further
characterization of endocrine disrupters and their influence on the risk of
uterine leiomyoma formation, including the effect of time of exposure (fetal,
neonatal, pubertal or adult) and dose relationships on the initiation or
exacerbation of uterine leiomyoma development;
o Assessment of whether growth factor expression is the framework through
which abnormal myometrial cellular and extracellular growth can be explored
to clarify the interaction between estrogen/progesterone and growth factors
and/or environmental exposures on uterine leiomyoma initiation and
development;
o Identification of noninvasive biomarkers to delineate molecular alterations
at specific stages of tumor development and definition of molecular markers
for uterine leiomyoma progression and recurrence;
o Facilitation of collaborative molecular studies through the establishment
of a tissue bank;
o Development of new avenues for diagnostic and conservative treatment
modalities that target relevant hormonal pathways for uterine leiomyoma
formation, including the design of novel pharmaceutical agents directed at
these pathways;
o Examination of gene-environment relationships including an examination of
genetic polymorphisms in key pathways and the effects of various
environmental insults, such as the exposures to solvents, pesticides, water
disinfection byproducts, and metals singly or in mixtures in the initiation
or exacerbation of uterine leiomyoma. These studies may include
transgenerational effects as well as developmental vulnerability.
MECHANISM OF SUPPORT
This RFA will use the NIH individual research project grant (R01) 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. It also uses the modular budgeting
format. (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.
FUNDS AVAILABLE
The NICHD intends to commit approximately $2 million [Direct plus Facilities
and Administrative (F & A) costs] in FY 2003 to fund five to six new grants
in response to this RFA. The NIEHS intends to commit up to $600,000 [Direct
plus Facilities and Administrative (F&A) costs] in FY 2003 to fund up to two
grants with an emphasis on the role of environmental exposures on the
initiation or exacerbation of uterine leiomyoma. An applicant may request a
project period of up to five years and a budget for direct costs of up to
$250,000 per year. 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 NICHD and NIEHS 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.
ELIGIBLE INSTITUTIONS
You may submit an application 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
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.
SPECIAL REQUIREMENTS
Annual Investigator Meeting
After initiation of the program, the NICHD will sponsor a meeting to
encourage the exchange of information among investigators who participate in
this program. In the preparation of the budget for the grant application,
applicants should include travel funds for the meeting to be held in
Bethesda, Maryland. Applicants should also include a statement in the
applications indicating their willingness to participate in such a meeting.
WHERE TO SEND INQUIRIES
We encourage inquiries concerning this RFA 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 basic science and translational
scientific/research issues or general RFA matters to:
Estella Parrott, M.D., M.P.H.
Center for Population Research
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8B01, MSC 7510
Bethesda, MD 20892-7510
Telephone: (301) 496-6515
FAX: (301) 496-0962
Email: ep61h@nih.gov
o Direct your questions about the role of environmental agents or
environmental scientific/research issues to:
Jerrold Heindel, Ph.D.
Organs and Systems Toxicology Branch
Division of Extramural Research and Training
National Institute of Environmental Health Sciences
79 T.W. Alexander Drive
4401 Building
Research Triangle Park, NC 27709
Telephone: (919) 541-0781
FAX: (919) 541-0781
Email: heindelj@niehs.nih.gov
o Direct your questions about financial or grants management matters to:
Ms. Kathy Hancock
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8A17, MSC 7510
Bethesda, MD 20892-7510
Telephone: (301) 496-5482
FAX: (301) 480-4782
Email: kh47d@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, and telephone number of the Principal Investigator
o Names of other key personnel
o Participating institutions
o Number and title of this RFA
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 NIH staff to estimate the potential review workload and plan
the review.
The letter of intent is to be sent by the date listed at the beginning of
this document. The letter of intent should be sent to:
Estella Parrott, M.D., M.P.H.
Center for Population Research
National Institute of Child Health and Human Development
6100 Executive Boulevard, Room 8B01, MSC 7510
Bethesda, MD 20892-7510
Telephone: (301) 496-6515
FAX: (301) 496-0962
Email: ep61h@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
https://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive
format. For further assistance contact GrantsInfo, Telephone (301) 710-0267,
Email: GrantsInfo@nih.gov.
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.
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 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)
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.
PEER REVIEW PROCESS
Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the NICHD and NIEHS. 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 NIH 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 National Advisory Child Health and
Human Development Council and the National Advisory Environmental Health
Sciences 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 humans, animals,
or the environment, to the extent they may be adversely affected by the
project proposed in the application.
o 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.)
o DATA SHARING: The adequacy of the proposed plan to share data.
o 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: March 14, 2003
Application Receipt Date: April 14, 2003
Peer Review Date: June 2003
Council Review: September 2003
Earliest Anticipated Start Date: September 30, 2003
AWARD CRITERIA
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
MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components
involving Phase I and II clinical trials must include provisions for
assessment of patient eligibility and status, rigorous data management,
quality assurance, and auditing procedures. In addition, it is NIH policy
that all clinical trials require data and safety monitoring, with the method
and degree of monitoring being commensurate with the risks (NIH Policy for
Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12,
1998: https://grants.nih.gov/grants/guide/notice-files/not98-084.html).
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
(https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html);
a complete copy of the updated Guidelines is available at
https://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
https://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
https://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 https://grants.nih.gov/grants/stem_cells.htm and at
https://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
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 Nos. 93.864 and 93.113 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.