CHARACTERIZATION, BEHAVIOR AND PLASTICITY OF PLURIPOTENT STEM CELLS
RELEASE DATE: May 4, 2004
PA NUMBER: PA-04-101
The R01 portion of this funding opportunity has been replaced by PA-07-201,
which now uses the electronic SF424 (R&R) application for February 5, 2007
submission dates and beyond.
March 2, 2006 (NOT-OD-06-046) Effective with the June 1, 2006 submission date,
all R03, R21, R33 and R34 applications must be submitted through Grants.gov using
the electronic SF424 (R&R) application. Accordingly, this funding opportunity
expires on the date indicated below. A replacement R21 (PA-06-198) funding
opportunity announcement has been issued for the submission date of June 1, 2006
and submission dates thereafter.
See NOT-OD-06-048 for information on May 1, 2006 Submission Date for AIDS and
AIDS-related R03 and R21 Applications.
Expiration Date for R21 Non-AIDS Applications: March 2, 2006
Expiration Date for R21 AIDS and AIDS-Related Applications: May 2, 2006
Expiration Date for R01 Non-AIDS Applications: November 2, 2006
Expiration Date for R01 AIDS and AIDS-Related Applications: January 3, 2007
Department of Health and Human Services (DHHS)
PARTICIPATING ORGANIZATION:
National Institutes of Health (NIH)
(http://www.nih.gov)
COMPONENTS OF PARTICIPATING ORGANIZATION:
National Institute of Neurological Disorders and Stroke (NINDS)
(http://www.ninds.nih.gov)
National Institute on Deafness and Other Communication Disorders (NIDCD)
(http://www.nidcd.nih.gov/)
National Institute on Aging (NIA)
(http://www.nia.nih.gov/)
National Institute of Child Health and Human Development (NICHD)
(http://www.nichd.nih.gov/)
National Cancer Institute (NCI)
(http://www.nci.nih.gov/)
National Institute on Drug Abuse (NIDA)
(http://www.nida.nih.gov)
National Institute of Mental Health (NIMH)
(http://www.nimh.nih.gov/)
CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBERS: NINDS 93.853, NIDCD 93.173,
NIA 93.866, NICHD 93.929, NCI 93.396, NIDA 93.279, and NIMH 93.242.
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 Special Requirements
o Where to Send Inquiries
o Submitting an Application
o Supplementary Instructions
o Peer Review Process
o Review Criteria
o Award Criteria
o Required Federal Citations
PURPOSE
Stem cells appear to possess great plasticity, but the cellular mechanisms
regulating their behavior and fate are not understood. If these mechanisms
can be harnessed to obtain cells specifically required for therapy, diagnosis
or drug discovery, it may be possible to restore function to tissues and
organ systems that have been compromised by congenital disorders,
developmental malfunction, age, injury, disease or drug exposure. The
National Institute of Neurological Disorders and Stroke (NINDS), the National
Institute on Deafness and Other Communication Disorders (NIDCD), the National
Institute on Aging (NIA), the National Institute of Child Health and Human
Development (NICHD), the National Cancer Institute (NCI), the National
Institute of Drug Abuse (NIDA), and the National Institute of Mental Health
(NIMH) invite applications for studies on the characterization, behavior and
plasticity of human and non-human stem cells, regulation of their
replication, differentiation, integration and function in the nervous system,
and the identification and characterization of normal and tumor stem cells.
An understanding of intrinsic and extrinsic signals, especially those
involved in the stem cell niche, age-dependent processes and genetic factors
that govern the activities of pluripotent cells is crucial in order to
utilize them to develop safe and effective treatments for the restoration of
function, or to prevent their transformation into tumor-generating cells.
Although animal studies demonstrate that stem or progenitor cells can be
derived from a variety of tissues and from hosts of different ages, the
requirements and potential for differentiation of each type of pluripotent
cell appear to be unique. We lack a clear understanding of the intrinsic
properties that distinguish one population from another, and how these
populations differ in their response to similar conditions in vitro and in
vivo. This Program Announcement, which replaces PA-01-078 (Biology of Non-
Human Stem Cells in the Environment of the Nervous System) and PA-02-025
(Plasticity of Human Stem Cells in the Nervous System), encourages
applications to study the fundamental properties of all classes of human and
non-human stem cells, and to confirm, extend, and compare the behavior of
stem cells that are derived from different sources and ages or exposed to
different regimes in vitro and in vivo or derived from tumors. Of high
priority are studies to develop methods for identifying, isolating and
characterizing specific precursor populations at intermediate stages of
differentiation into neurons and glia, and their relationship to tumor-
generating cells. Projects that address comparisons between different classes
of human stem cells and between human and non-human stem cells would also be
directly relevant to this PA.
RESEARCH OBJECTIVES
Background
Stem cell research offers enormous potential for treating a host of
congenital, developmental, psychiatric or degenerative diseases for which
there are no cures. In animal studies, multipotent progenitor cells from many
different sources have been reported to generate cells with neuronal or glial
properties, raising expectations that they could be used to replace lost
neurons and glia, repair defective circuits, and restore functions
compromised by abnormal development, age, physical damage, disease or drug
addiction. In addition to cell and tissue therapy, the ability to selectively
produce one or more differentiated cell types at will from pluripotent stem
cells would be of clinical importance in investigating the effects of drugs,
environmental and genetic factors on differentiation and cell function in the
human nervous system. These approaches could aid in the discovery of drugs
and ultimately in the development of a variety of effective treatment
strategies.
Major challenges have to be overcome before any type of stem cell can be
harnessed and translated to meaningful treatments for patients. These
challenges include identifying the optimal type of stem cell or stem cell
derivative for specific assays and therapies for individual disorders,
harvesting and growing sufficient quantities of the appropriate cell type,
deciding the best therapeutic strategy for each condition to be treated, and
assessing the potential side effects that may arise when such versatile cells
are introduced into a patient. In addition, examples of the enormous
plasticity exhibited by stem cells raise fundamental questions about the
comparative potential for differentiation of precursor cells derived from
different sources and different stages of development, the nature of the
conditions that regulates stem cell behavior, and the genetic, molecular and
cellular mechanisms that result in functional integration within the nervous
system over the lifespan of the host.
Of the many types of progenitor cells competent to develop neuronal and glial
features, embryonic stem (ES) cells, derived from embryos at the blastocyst
stage, may have the broadest natural potential for differentiation because,
during development, they normally produce all the cells of an organism. These
pluripotent cell lines are characterized by nearly unlimited self-renewal and
differentiation capacity. During differentiation in vitro, mouse and human
ES cells express properties of mature tissues such as muscles, several
classes of neurons, glia, pancreatic islet cells, cartilage and blood. When
transplanted into the central nervous system (CNS), ES cells that have been
coaxed along an oligodendrocytic lineage will form myelin and ensheath axons.
Some improved function was reported in rodent models of demyelination and
spinal cord injury that received these ES cell-derived transplants. However,
how the transplanted cells contributed to the restoration of function is
unclear.
Other sources of progenitors are neural stem cells that are derived from
neurogenic regions in the developing and adult CNS. They integrate seamlessly
into the host when transplanted into the developing nervous system, but their
fate appears highly dependent upon the local environment that they encounter.
This is particularly true when these cells are introduced into the adult CNS.
For example, cells that can become neurons in one part of the nervous system,
such as the hippocampus, generate astrocytes exclusively when placed into the
spinal cord. The concept of the niche has emerged recently as an important
one; yet at the present time, we have very little information on the nature
of the environmental signals that regulate fate decisions of stem cells.
Of particular interest are recent reports from a number of investigators that
stem cells present in adult, non-neuronal tissues appear to show surprising
plasticity or versatility. For example, under specific culture conditions,
bone marrow stromal cells appear to trans-differentiate to give rise to
cells with neuronal or glial features. Following bone marrow
transplantation, donor-derived cells could be found in many tissues including
the CNS, skeletal muscle, liver, heart, vascular endothelia, and bone. Some
of these findings have been attributed to the fusion of a donor cell with a
mature host cell, giving the appearance of trans-differentiation of the donor
cell to an unrelated adult phenotype. Other reports of switches in lineage
cannot be explained by fusion. Perhaps most intriguing is the hypothesis
that cells committed to a particular lineage may de-differentiate to a more
pluripotent state. One of the most attractive sequelae of plasticity is the
possibility of developing autologous cells for transplantation, because
autologous grafts will not be rejected by the host or recipient. On the other
hand, the pliable nature of stem cells raises the concern that transplanted
cells could be triggered by the local environment to an undesired phenotype
with unpredictable consequences. Before we can design therapies using human
stem cells, we must understand how "plastic" or malleable are these different
classes of cells, the signals that drive their choice of fates, and how
reversible are these fates.
For unknown reasons, select populations of cells are destroyed in specific
neurological disorders and diseases - dopaminergic neurons in Parkinson's
Disease (PD), cholinergic neurons in Alzheimer's Disease(AD), motor neurons
in Amyotrophic Lateral Sclerosis (ALS) and myelinating oligodendrocytes in
Multiple Sclerosis (MS). Because there is great diversity of neurons and
glia, studies to develop treatments for these and other diseases with less
well defined etiologies will require the characterization and acquisition of
unique populations of neurons and glia. While dopaminergic neurons are
clearly the target of studies on PD, defining the specific features of the
dopaminergic neurons needed to treat PD is less obvious. Each neuronal and
glial phenotype is defined by a constellation of morphological, biochemical,
genetic, and electro-physiological properties, and the functional
significance or impact of a neuronal population depends on connectivity with
appropriate afferent and efferent populations. It is necessary to determine
the optimal stem cell and protocol that will produce a differentiated
phenotype that best replicates the significant properties required and can
replace the dysfunctional cell type. The features most commonly evaluated
include morphology, biochemical and gene expression, and physiology. Less
often described are quantification of protein and gene levels, acquisition
and maintenance of phenotype over time, cell division and migration, and the
simultaneous tracking of multiple properties in a population of cells. Least
studied are the integration and functional consequences of the transplanted
cells in the host, and the long-term behavior of the transplanted population.
In summary, because we know little about the biology and the comparative
scope for differentiation of the many different types of stem cells, it is
difficult to assess realistically their potential for use in developing
treatments for neurological disease and other conditions.
Recent findings demonstrate that in select regions of the avian and mammalian
nervous systems, endogenous neural stem and precursor cells continue to
produce new neurons and circuits throughout adulthood, and indeed over the
entire lifespan, though new cell production declines with age. In the adult
hippocampus, newly born neurons acquire the size and morphology of their
older neighbors and establish contacts with existing circuits in the brain, a
process that can take months to complete. Endogenous stem cells can replace
hair cells of the inner ear following acoustic and drug-induced damage in the
adult avian and amphibian nervous systems. Similarly, the sensory neurons of
the olfactory epithelium are replaced on a regular basis, and especially in
response to injury, from an endogenous stem cell pool. Behavior, experience
and drugs such as anti-depressants have demonstrable and profound effects on
the production and establishment of new neurons in the adult and the aging
brain. Drug abuse, on the other hand, have been shown to inhibit neurogenesis
in rodents and result in developmental deficits and cognitive dysfunctions in
humans and animals. All these findings have important implications for
development, learning, memory and the maintenance of a healthy nervous system
that functions throughout life. New research into mechanisms that influence
ongoing neurogenesis and gliogenesis will provide fundamental information on
the capacity of the nervous system to adapt in response to pharmacological
and behavioral therapy throughout life. The hope is that processes that
regulate the native production and integration of new neurons may be deployed
to repair disordered regions of the brain.
Objectives and Scope
This Program Announcement is intended to promote studies of stem cell
biology and the regulation and control of stem cells in the nervous system.
Research efforts on characteristics that distinguish between different types
of stem cells and the cellular, molecular and genetic mechanisms that
influence their lineage choices are particularly relevant, as are studies
that explore the long-term fates of stem cell-derived populations in animal
models. Also of interest is the development of methods for isolating specific
cell populations, and studies that demonstrate or enhance the safety of stem
cells in treatments for neurological conditions. The following examples
illustrate areas that are of high interest; other innovative projects are
also encouraged.
o Comparison of the mitotic potential and fates of different types of
pluripotent, progenitor cells in vitro and in vivo.
o Comparison of the migratory properties and structural and functional
integration of different types of progenitor cells in the developing, adult
or aging host nervous system.
o Comparison of the behavior of human stem cells with that of their non-
human counterparts in vitro and in vivo.
o Investigation of the ability of different types of stem cells or of
partially differentiated cells to revert to a more plastic, multipotent
state, under normal conditions and following injury, disease or drug
exposure.
o Examination of changes in gene and protein expression as human and animal
stem cells differentiate along specific lineages.
o Identification of signals, signaling pathway components and transcriptional
factors that regulate the fate(s) of transplanted stem cells and their
progeny in the nervous system of the host.
o Development of markers and assays (in vitro and in vivo) that permit
accurate and reliable characterization of the state of differentiation of
human and non-human stem or neural precursor cells.
o Development of methods for identifying, isolating and enriching select
precursor populations, intermediate states, and differentiated neuronal and
glial phenotypes.
o Development of a public database of gene expression patterns for human and
non-human stem cells as they self-renew or develop and mature into specific
neuronal and glial fates.
o Use of animal model systems of neurological and neuropsychiatric disorders
and of drug addiction for screening and comparing the functional capabilities
of implanted stem cells and their progeny.
o Assessment of the ability of transplanted cells to integrate with the adult
and aging host nervous system and modify dysfunctional states.
o Assessment of the long-term fates and the consequences of transplanted
cells and their progeny in the nervous system, and in ectopic sites within
the host.
o Assessment and comparison of the immune responses generated by different
human stem cells and their progeny in the host.
o Assessment of the behavior of host cells in response to the short-term and
long-term presence of transplanted human stem cells and/or their derivatives.
o Comparison of the efficacy and risks of different modes of cell delivery in
large and small mammals, and in animals of different ages.
o Development of novel techniques such as non-invasive methods to track the
location, phenotype, integration and/or function of transplanted stem cells
and their progeny.
o Assessment of the effects of environmental changes, therapies, or
rehabilitation strategies on the production, differentiation and survival of
endogenous stem cells across the lifespan.
MECHANISM OF SUPPORT
The Exploratory/Developmental Grants (R21) mechanism and the Research Project
(R01) grant mechanism will be used to support projects under this Program
Announcement (PA). Under these mechanisms, responsibility for the planning,
direction, and execution of the proposed project will be solely that of the
applicant. The proposed project period during which the research will be
conducted should adequately reflect the time required to accomplish the
stated goals and should be no more than 5 years for R01 grants. The R21
mechanism (see http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html)
is intended to encourage exploratory and developmental research projects by
providing support for the early and conceptual stages of these projects.
These one-time awards support innovative, high impact research projects that
1) assess the feasibility of a novel area of investigation or a new
experimental system, 2) include the unique and innovative use of an existing
methodology to explore a new scientific area, 3) involve considerable risk
but may lead to a breakthrough in a particular area, or 4) develop new
technology or methodology that could have major impact in a specific research
area. Applications for R21 awards should describe projects distinct from
those supported through the traditional R01 mechanism. For example, long-
term projects, or projects designed to increase knowledge in a well-
established area will not be considered for R21 awards. Applications
submitted under this mechanism should be exploratory and novel. These
studies should break new ground or extend previous discoveries toward new
directions or applications.
R21 applications may request a project period of up to two years with a
combined budget for direct costs of up to $275,000 for the two year period.
For example, you may request $100,000 in the first year and $175,000 in the
second year. The request should be tailored to the needs of your project.
Normally, no more than $200,000 may be requested in any single year. For
further information on the R21 mechanism, including Institute-specific
information,see http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html.
This PA uses just-in-time concepts. It also uses the modular budgeting 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 budget format. Otherwise follow the instructions
for non-modular budget research grant applications.
ELIGIBLE INSTITUTIONS
You may submit (an) application(s) if your institution has any of the
following characteristics:
o For-profit or non-profit organizations
o Public or private institutions, such as universities, colleges, hospitals,
and laboratories
o Units of State and local governments
o Eligible agencies of the Federal government
o Domestic or foreign institutions/organizations
INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS
Any individual with the skills, knowledge, and resources necessary to carry
out the proposed research is invited to work with their institution to
develop an application for support. Individuals from underrepresented racial
and ethnic groups as well as individuals with disabilities are always
encouraged to apply for NIH programs.
SPECIAL REQUIREMENTS
Use of human embryonic stem cells (hESCs): Criteria for federal funding of
research on hESCs can be found at
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.
All cell lines that meet these criteria and are therefore eligible for
research with federal funding are identified and registered in the NIH Human
Embryonic Stem Cell Registry (http://escr.nih.gov). NIH has established a
website (http://stemcells.nih.gov/info/faqs.asp) that provides
information in the form of answers to frequently asked questions about
implementation issues for human embryonic stem cell research (see also:
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-014.html). Only
research using hESC lines that are registered in the NIH Human Embryonic Stem
Cell Registry will be eligible for funding. Each approved cell line is
specifically identified by an NIH code in the Registry. It is the
responsibility of the applicant to provide in the Description (page 2) of
their application the official NIH identifier(s) for the hESC line(s) that
they will use as found in the NIH Registry (http://escr.nih.gov).
Applications that do not provide this information will be returned without
review.
Plan for Dissemination of Data and Biomaterials: Sharing of biomaterials,
data, and software in a timely manner is essential for rapid progress in
biomedical research. All applicants who respond to this PA must propose
plans for sharing data and biomaterials generated through the grant. PHS
policy requires that investigators make unique research resources available
for research purposes to qualified individuals within the scientific
community when they have been published (see the NIH Grants Policy Statement
at http://grants.nih.gov/grants/guide/notice-files/not96-184.html).
In addition, NIH recently released a statement on the sharing of research
data that applies to all investigator-initiated applications with direct
costs greater than $500,000 in any single year
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html).
The Initial Review Group will evaluate the proposed sharing plan and comment
on its adequacy in an administrative note in the summary statement.
Reviewers will not factor the proposed data-sharing plan into the
determination of scientific merit or priority score. The adequacy of the
plan will be considered by NIH staff in determining whether the grant shall
be awarded. The sharing plan as approved, after negotiation with the
applicant when necessary, will be a condition of the award.
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:
Arlene Y. Chiu, Ph.D.
Program Director, Repair and Plasticity Program
National Institute of Neurological Disorders and Stroke
Neuroscience Center, Room 2206, MSC 9525
Bethesda, MD 20892-9525
Telephone: (301) 496-1447
FAX: (301) 480-1080
Email: chiua@ninds.nih.gov
Barry J. Davis, Ph.D.
Division of Scientific Programs
NIDCD / Suite 400C
6120 Executive Blvd., MSC 7180
Rockville, MD 20892-7180
Phone: 301-402-3464
FAX: 301-402-6251
Email: Davisb1@nidcd.nih.gov
Bradley C Wise, Ph.D.
Program Director, Fundamental Neuroscience
Neuroscience and Neuropsychology of Aging Program
National Institute on Aging
Gateway Building, Suite 350
7201 Wisconsin Avenue MSC 9205
Bethesda, MD 20892-9205
Telephone: (301) 496-9350
FAX: (301) 496-1494
Email: WiseB@nia.nih.gov
Ralph M. Nitkin, Ph.D.
Biological Sciences and Career Development Program
National Center for Medical Rehabilitation Research
National Institute of Child Health and Human Development
Executive Building, Room 2A03
6100 Executive Blvd, MSC 7510
Bethesda, MD 20892-7510
Telephone: (301) 402-4206
FAX: (301) 402-0832
Email: rn21e@nih.gov
Neeraja Sathyamoorthy, Ph.D.
Program Director
Tumor Biology & Metastasis Branch
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard EPN 5036
Rockville MD 20892
Phone: 301-435-1878
Fax: 301-480-0864
Email: ns61r@nih.gov
Geraline C. Lin, Ph.D.
Division of Neuroscience and Behavioral Research
National Institute on Drug Abuse
6001 Executive Boulevard
Room 4282, MSC 9555
Bethesda, MD 20892-9555
Telephone: (301) 435-1305
FAX: (301) 594-6043
Email: glin@nida.nih.gov
Beth-Anne Sieber, Ph.D.
Chief, Developmental Neurobiology Program
National Institute of Mental Health
Division of Neuroscience and Basic Behavioral Science
6001 Executive Boulevard, Rm 7186
Bethesda, MD 20892-9641
Phone: (301) 443-5288
Fax: (301) 402-4740
E-mail: bsieber@mail.nih.gov
o Direct your questions about financial or grants management matters to:
Michael J. Loewe
Chief, Grants Management Branch
National Institute of Neurological Disorders and Stroke
6001 Executive Blvd., Suite 3290, MSC 9537
Bethesda, MD 20892-9537
Telephone: (301) 496-9231
FAX: (301) 402-0219
Email: ml70m@nih.gov
Or to
Gavin Wilkom
Grants Management Specialist
Grants Management Branch, DER
National Institute of Neurological Disorders and Stroke
Neuroscience Center, 6001 Executive Blvd. Room 3250, MSC 9537
Bethesda MD, 20892
Telephone: (301) 496-7480
FAX: 301-402-0219
Email: gw62m@nih.gov
Sara Stone
Chief, Grants Management Office
Division of Extramural Activities
NIDCD / Suite 400B
6120 Executive Blvd, MSC-7180
Bethesda, MD 20892-7180
Telephone: (301)402-0909
FAX: (301) 4021758
Email: stones@nidcd.nih.gov
Linda Whipp
Grants Management Officer
Grants and Contracts Management Office
National Institute on Aging
7201 Wisconsin Avenue, Suite 2N212 MSC9205
Bethesda, Maryland 20892-9205
Telephone: (301) 496-1472
Email:WhippL@nia.nih.gov
Chris Robey
Grants Management Branch
National Institute of Child Health and Human Development
6100 Executive Boulevard, 8A17, MSC 7510
Bethesda, MD 20892-7510
Telephone: (301) 435-6996
FAX: (301) 451-5510
Email: robeyj@mail.nih.gov
Bill Wells
Grants Administration Branch
National Cancer Institute
EPS Room 243
6130 Executive Boulevard
Rockville MD 20892
Phone: 301-496-8796
Email: wellsw@mail.nih.gov
Diana Haikalis
Acting Team Leader
Grants Management Branch
National Institute on Drug Abuse
6101 Executive Boulevard
Room 270 MSC 8403
Bethesda, MD 20892-8403
Telephone: (301) 443-6710
Email: dhaikali@nida.nih.gov
Rebecca Claycamp, CRA
Chief Grants Management Officer
National Institute of Mental Health
6001 Executive Boulevard, Room 6122, MSC 9605
Bethesda, MD 20892-9605
Telephone: (301) 443-2811
FAX: (301) 443-6885
Email: rc253d@nih.gov
SUBMITTING AN APPLICATION
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 http://www.dunandbradstreet.com/. The DUNS number
should be entered on line 11 of the face page of the PHS 398 form. 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) 710-0267, Email: GrantsInfo@nih.gov.
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.
SUPPLEMENTARY INSTRUCTIONS: All instructions for the PHS 398 (rev. 5/2001)
must be followed, with these exceptions:
o Description (page 2)
The NIH identifier(s) of the hESC line(s) to be used must be included.
o Research Plan
For R21 applications only, items a d of the Research Plan (Specific Aims,
Background and Significance, Preliminary Studies, and Research Design and
Methods) may not exceed a total of 15 pages. No preliminary data is required
for R21 proposals, but may be included if it is available. Please note that
a Progress Report is not needed for R21 awards; competing continuation
applications for an exploratory/developmental grant will not be accepted.
Appendix. Use the instructions for the appendix detailed in the PHS 398
except that for R21 applications, no more than 5 manuscripts, previously
accepted for publication, may be included.
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 BUDGET GRANT APPLICATIONS: Applications
requesting 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 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 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 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.
PEER REVIEW PROCESS
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
(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 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
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 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
application.
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, below).
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm
INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: 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 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.
ADDITIONAL REVIEW CONSIDERATIONS
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.
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
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.
http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm
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:
http://grants.nih.gov/grants/guide/notice-files/not98-084.html).
SHARING RESEARCH DATA: 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.
http://grants.nih.gov/grants/policy/data_sharing 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.
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 "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.
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://stemcells.nih.gov/index.asp 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, 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.
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.
STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The
Department 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).
Decisions about applicability and implementation of the Privacy Rule reside
with the researcher and his/her institution. The OCR website
(http://www.hhs.gov/ocr/) 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
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.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. 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.healthypeople.gov/.
AUTHORITY AND REGULATIONS: This program is described in the Catalog of
Federal Domestic Assistance at http://www.cfda.gov/ 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
http://grants.nih.gov/grants/policy/policy.htm
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
|
|
|
|
Department of Health and Human Services (HHS)
|
|
|
|
NIH... Turning Discovery Into Health®
|