[Federal Register Volume 67, Number 226 (Friday, November 22, 2002)]
[Notices]
[Pages 70417-70420]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-29751]


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DEPARTMENT OF ENERGY


Office of Science Financial Assistance Program Notice 03-14; 
Radiopharmaceutical and Molecular Nuclear Medicine Science Research--
Medical Applications Program

AGENCY: Department of Energy.

ACTION: Notice inviting grant applications.

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SUMMARY: The Office of Biological and Environmental Research (OBER) of 
the Office of Science (SC), U.S. Department of Energy (DOE), hereby 
announces its interest in receiving grant applications for research to 
support DOE/OBER Medical Applications Program areas in 
radiopharmaceuticals and molecular nuclear medicine. These program 
areas involve multifunctional, highly designed tracer molecules for 
precise in vivo tagging and noninvasive imaging assay of cellular and 
subcellular elements at the dynamic organ function, onset and 
progression of disease, and response to successful or failing therapy.
    Research areas of particular programmatic interest include:
    1. New tracer technologies for real-time, in vivo imaging of gene 
expression in health and disease.
    2. New radiotracer labeling of progenitor cells for noninvasively 
imaging and tracking their behavior and fate in vivo and their overall 
role in organ and tissue regeneration in disease states.
    3. New radiotracers for in vivo targeting of mutated proteins 
critical to carcinogenesis and tumor cell growth.
    4. New generation of radiotracers enabling in vivo imaging assay of 
neurotransmitter chemistry and brain function.

DATES: Preapplications (letters of intent), including information on 
collaborators, and a one-page summary of the proposed research, should 
be submitted by January 2, 2003.
    Formal applications submitted in response to this notice must be 
received by 4:30 p.m., E.S.T., Monday, February 24, 2003, in order to 
be accepted for merit review and to permit timely consideration for 
award in Fiscal Year 2003.

ADDRESSES: Preapplications referencing Program Notice 03-14, should be 
sent to Ms. Sharon Betson by E-mail: [email protected], 
with a copy to Dr. Prem C. Srivastava at: 
[email protected].
    Formal applications in response to this solicitation are to be 
electronically submitted by an authorized institutional business 
official through DOE's Industry Interactive Procurement System (IIPS) 
at: http://e-center.doe.gov/. IIPS provides for the posting of 
solicitations and receipt of applications in a paperless environment 
via the Internet. In order to submit applications through IIPS your 
business official will need to register at the IIPS website. The Office 
of Science will include attachments as part of this notice that provide 
the appropriate forms in PDF fillable format that are to be submitted 
through IIPS. Color images should be submitted in IIPS as a separate 
file in PDF format and identified as such. These images should be kept 
to a minimum due to the limitations of reproducing them. They should be 
numbered and referred to in the body of the technical scientific 
application as Color image 1, Color image 2, etc. Questions regarding 
the operation of IIPS may be E-mailed to the IIPS Help Desk at: 
center.doe.gov">HelpDesk@e-center.doe.gov or you may call the help desk at: (800) 683-
0751. Further information on the use of IIPS by the Office of Science 
is available at: http://www.sc.doe.gov/production/grants/grants.html.
    If you are unable to submit an application through IIPS please 
contact the Grants and Contracts Division, Office of Science at: (301) 
903-5212 in order to gain assistance for submission through IIPS or to 
receive special approval and instructions on how to submit printed 
applications.

FOR FURTHER INFORMATION CONTACT: Dr. Prem C. Srivastava, Office of 
Biological and Environmental Research, Medical Sciences Division, U.S. 
Department of Energy, SC-73/Germantown Building, 1000 Independence 
Avenue SW., Washington, DC 20585-1290, Telephone: (301) 903-4071, FAX: 
(301) 903-0567, E-mail: [email protected]. The full text 
of Program Notice 03-14 is available via the Internet using the 
following web site address: http://www.sc.doe.gov/production/grants/Fr03-14.html.

SUPPLEMENTARY INFORMATION: For over 50 years, the Department's Office 
of Science and its predecessors have supported basic physical science 
research for meeting the Nation's defense and security needs. The SC's 
Office of Biological and Environmental Research program has served as 
the Department's primary research arm for addressing the health and 
environmental consequences and potential public pay-offs of atomic 
energy explorations and use by translating the fundamental energy 
science to basic technology innovations and development for medical 
applications. Along the way, the OBER's Medical Applications program 
has leveraged the Department's unique capabilities in radiation 
chemistry, physics, engineering, computation, and biology, together 
with capabilities in and responsibilities for radiation detection and 
nuclear materials to support basic, high-risk research that today 
provides the upstream basis to use radiation and other energy 
technologies in medicine.
    The mission of the OBER Medical Applications subprogram is to 
deliver relevant scientific knowledge that will lead to innovative 
diagnostic and treatment technologies for human health. The basic 
research technologies growing out of this program offer applications 
for noninvasive detection, diagnosis and early intervention of natural 
causes of disease, as well as of human-health-risks associated with the 
exposure of chemical, biological and nuclear material.
    The modern era of nuclear medicine is an outgrowth of the original 
charge of the Atomic Energy Commission (AEC), ``to exploit nuclear 
energy to promote

[[Page 70418]]

human health.'' Today the program through radiopharmaceutical, 
molecular nuclear medicine and multimodal imaging systems research, 
seeks to develop new applications of radiotracers and radionuclide 
detectors in diagnosis and treatment by integrating the latest concepts 
and developments in chemistry, pharmacology, genomic sciences and 
transgenic animal models, structural, computational and molecular 
biology, and instrumentation.
    The Medical Applications program supports directed nuclear medicine 
research through radiopharmaceutical development, molecular nuclear 
medicine and medical imaging instrumentation program activities to 
study uses of radioisotopes for non-invasive diagnosis and targeted, 
internal molecular radiotherapy. Molecules directing or affected by 
homeostatic controls always interact and, thus, are targets for 
specific molecular substrates. The substrate molecules can be tailored 
to fulfill a specific need and labeled with appropriate radioisotopes 
to become measurable in real time in the body on their way to, and in 
interaction with their targets allowing the analysis of molecular 
function in homeostatic control in health and disease. The function of 
radiopharmaceuticals at various sites in the body is imaged by nuclear 
medical instruments, such as gamma cameras and positron emission 
tomographs (PET). This type of imaging refines diagnostic 
differentiation at molecular/metabolic levels between health and 
disease, and among various diseases, often leading to more effective 
therapy.
    Basic research in molecular biology has provided new insights to 
the molecular basis of disease and molecular targets of human diseases. 
The current Radiopharmaceutical and Molecular Nuclear Medicine programs 
encourage development of new generation of radiolabeled molecules and 
technologies for molecular delivery of radioisotopes to the disease-
target-sites with a high degree of precision, recognition, and target 
selectivity.
    In addition, nuclear medicine, with the availability of 
miniaturized PET technology for small animal imaging, can facilitate 
mapping of the biochemistry of the metabolic organ function, 
visualizing the molecular biology of cell function, and zooming in on 
gene function for delineating differences in molecular biology of 
normal health from disease, in animals to humans.
    With the advent of the genome project and the development of 
transgenic mice, there has been a rapid proliferation of small animal 
models of human diseases, and improvement in instrumentation 
technologies for in vivo optical and radionuclide imaging. These 
technological advancements have offered a paradigm shift in the current 
level of nuclear medicine research challenges and opportunities. It is 
expected that radiopharmaceutical and molecular nuclear medicine 
techniques will permit analysis of the molecular elements as markers of 
genetic manipulations, biological transformations and progression of 
the disease, and will provide insights to molecular pathways of disease 
and gene function.
    This Notice is to solicit applications for grants in any of the 
four research areas of interest to OBER Medical Applications program 
listed above.
    Imaging Gene Expression in Health and Disease: The specific goals 
include development of nuclear medicine driven technologies to image 
mRNA transcripts in real time in tissue culture and whole animals. 
Special consideration will be given to applications arising from a well 
integrated, multidisciplinary team effort of scientists with skills to 
address the needs, issues and importance of nucleic acid biochemistry, 
radioligand synthesis and macromolecular interactions; functional 
consequences of gene expression by targeting and perturbing the 
activity of a particular gene; and biological applications of optical 
and radionuclide imaging devices; contributing to the goal of imaging 
specific gene expression in real time in animals to humans. The access 
to, or availability of specialized molecular radioligands, transgenic 
animal models of human disease, and biological imaging devices for real 
time imaging in animals to humans, will be important factors for 
funding considerations. Methodological approaches that are applicable 
to any mRNA species are encouraged. The development of generic methods 
to image specific gene expression will result in major advances in our 
understanding of developmental biology, cancer induction and 
pathogenesis, and in the clinical detection of inherited and acquired 
diseases. Such studies are therefore one of the major focus areas of 
this program. Currently the expression of endogenous genes in animals 
(including humans) cannot be imaged, at least not directly. A well 
integrated team effort from the overlapping disciplines of chemistry 
and radiopharmaceutical chemistry, cellular and molecular biology, and 
biological and nuclear medicine imaging will be increasingly important. 
It will be important for each application to address response in view 
of the following research areas, which may be crucial for progress in 
imaging gene expression:
    (1) New generation of radioligand molecules that will interact with 
the macromolecular nucleic acid structures in vivo.
    (2) Molecular technologies which will significantly improve the 
signal to background ratio and will make in vivo imaging feasible. 
Molecular signal amplification methods are not yet available that work 
in vivo at the mRNA level and technological advancement in this area is 
well desired.
    (3) Equally important is the hurdle of drug targeting technology, 
which must be developed to such an extent that the various biological 
barriers can be safely surmounted in vivo.
    (4) Finally, the fluorescent molecular imaging technologies 
available for more routine in vitro screening and in vivo real time 
imaging, that can be used as a proof of principle and a prelude to in 
vivo nuclear medicine imaging, should be exploited in conjunction with 
nuclear medicine devices.

Radiopharmaceutical Research for Noninvasive Radiotracer-Cell Imaging 
(NRI) In Vivo

    Progenitor Cells: The term progenitor cells implies non-embryonic 
stem cells, and does not include embryonic stem cells. For definitions, 
refer to National Institutes of Health (NIH) web sites, and all 
grantees must adhere to federal guidelines when involving human 
subjects. http://www.nih.gov/news/stemcell/primer.htm and http://www.nih.gov/news/stemcell/index.htm.
    Breakthrough research in the biology of inter-organ and tissue cell 
repopulation and transformation has offered new paradigms for 
radiotracer imaging research in resolving the issues of progenitor cell 
administration including their trafficking, biodistribution, fate and 
progeny in organ and tissue regeneration, repair and replacement, with 
wide applications to human disease states such as neurogenesis, 
myogenesis, hematopoiesis, including stroke, ischemic heart disease, 
Parkinson's disease, hematopoetic disorders and cancers. This NRI 
specific program announcement offers challenging research opportunities 
for new radiotracer technology innovations for emerging new clinical 
research needs and medical applications.
    The specific goals include radiotracer labeling of progenitor cells 
for noninvasively imaging and tracking their behavior and fate in vivo 
and their overall role in organ and tissue

[[Page 70419]]

regeneration in disease states. The researchers should clearly 
demonstrate the relevance and important clinical need of the research 
proposed. Special consideration will be given to applications arising 
from a well-integrated, multidisciplinary team effort of scientists 
with relevant skills in radiopharmaceutical chemistry, biology, 
pharmacology and clinical nuclear medicine. The access to, or 
availability of specialized radiotracer-labeling and imaging 
instrumentation, equipment and facilities for real time imaging in 
animals to humans, will be important factors for funding 
considerations.

New Radiotracers for Targeting Mutated Proteins Critical to 
Carcinogenesis and Tumor Cell Growth

    Radiolabeled molecular probes for targeting protein mutations 
critical to carcinogenesis and tumor cell growth would be unique tools 
for in vivo measuring of kinase pathways, for early diagnosis of 
cancer, for monitoring cancer therapy, and for understanding the 
mechanism of action of drugs targeting protein kinase activity in the 
development of new therapeutic drugs. Important therapeutic agents are 
being developed based on their specificity for protein kinases 
critically involved in intracellular signaling pathways, and there are 
likely to be about two thousand protein kinases encoded by the human 
genome. In recent years several small molecules have been identified to 
exhibit high degree of specificity for particular protein kinases, and 
a myriad of other compounds have also been identified as inhibitors of 
receptor tyrosine kinases and of mitogen-activated protein kinase 
cascades. Interaction of these compounds with these key kinases results 
in blockade of signal transduction and inhibition of cell cycle 
progression. This knowledge has resulted in the discovery of molecules 
with high specificity for several protein kinases and has provided a 
new view to cancer treatment. It also provides a challenging 
perspective for in vivo quantification of these intracellular pathways 
controlling cell proliferation and critically involved in cancer 
progression.
    The Department, through its synchrotron light sources facilities, 
contributes significantly to genomics/proteomics, i.e. protein analysis 
and structural genomics, and allows the structural biologists to find 
the specific parts of the protein structure that are most vulnerable to 
drugs or that may be key to carcinogenesis. The Department's 
investments in biophysics, chemistry, robotics and supercomputing, have 
made it possible to rapidly investigate the detailed arrangements of 
atoms and understand the function of thousands of proteins whose 
structures are coded by the genome of animals, bacteria and plants. 
Harnessing of the structural genomics/proteomics information will be a 
key to designing new small radiotracer molecules for precisely 
targeting the vulnerable areas of a mutated protein structure 
expressing cancer. Radiotracer molecules like these will be useful in 
laboratory investigations, and validation as molecular imaging probes 
for early diagnosis of cancer and management of cancer therapeutics.
    New generation of radiotracers enabling in vivo imaging assay of 
neurotransmitter chemistry and brain function: New generation of highly 
innovative and target specific radiotracer molecules are required as 
diagnostic markers for noninvasively imaging the regional biochemistry 
associated with metabolic organ function and performance, for guiding 
surgery, and for guiding new drug development.

Program Funding

    It is anticipated that up to $4 million will be available for 
multiple grant awards during Fiscal Year 2003, contingent upon the 
availability of appropriated funds. Previous awards have ranged from 
$200,000 up to $400,000 per year (direct plus indirect costs) with 
terms lasting up to three years. Similar award sizes are anticipated 
for new grants. Applications may request project support up to three 
years, with out-year support contingent on the availability of funds, 
progress of the research and programmatic needs.

Preapplications

    A brief preapplication (letter of intent) should be submitted. The 
preapplication should identify, on the cover sheet, the title of the 
project, the institution, principal investigator's name, address, 
telephone, fax, and E-mail address. The preapplication should consist 
of one to two pages identifying and describing the research objectives, 
methods for accomplishment, and the key members of the scientific team 
responsible for undertaking this effort, including information on 
collaborators. Preapplications will be evaluated relative to the scope 
and programmatic research needs.

Merit Review

    Applications will be subjected to scientific merit review (peer 
review) and will be evaluated against the following evaluation criteria 
listed in descending order of importance as codified at 10 CFR 
605.10(d):
    1. Scientific and/or Technical Merit of the Project;
    2. Appropriateness of the Proposed Method or Approach;
    3. Competency of Applicant's Personnel and Adequacy of Proposed 
Resources;
    4. Reasonableness and Appropriateness of the Proposed Budget.
    The evaluation will include program policy factors such as the 
relevance of the proposed research to the terms of the announcement and 
the agency's programmatic needs. Note, external peer reviewers are 
selected with regard to both their scientific expertise and the absence 
of conflict-of-interest issues. Non-federal reviewers may be used, and 
submission of an application constitutes agreement that this is 
acceptable to the investigator(s) and the submitting institution.

Submission Information

    Information about the development, submission of applications, 
eligibility, limitations, evaluation, the selection process, and other 
policies and procedures may be found in 10 CFR Part 605, and in the 
Application Guide for the Office of Science Financial Assistance 
Program. Electronic access to the Guide and required forms is made 
available via the World Wide Web at: http://www.sc.doe.gov/production/grants/grants.html. DOE is under no obligation to pay for any costs 
associated with the preparation or submission of applications if an 
award is not made.
    In addition, for this Notice, the Project Description must be 20 
pages or less, exclusive of attachments, and the application must 
contain a Table of Contents, an abstract or project summary, letters of 
intent from collaborators (if any), and short curriculum vitae 
consistent with National Institutes of Health guidelines. On the SC 
grant face page, form DOE F4650.2, in block 15, also provide the PI's 
phone number, fax number, and E-mail address.
    DOE policy requires that potential applicants adhere to 10 CFR 745 
``Protection of Human Subjects'', or such later revision of those 
guidelines as may be published in the Federal Register.
    The Office of Science as part of its grant regulations requires at 
10 CFR 605.11(b) that a recipient receiving a grant and performing 
research involving recombinant DNA molecules and/or organisms and 
viruses containing recombinant DNA molecules shall

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comply with NIH ``Guidelines for Research Involving Recombinant DNA 
Molecules,'' which is available via the world wide web at: http://www.niehs.nih.gov/odhsb/biosafe/nih/rdna-apr98.pdf, (59 FR 34496, July 
5, 1994,) or such later revision of those guidelines as may be 
published in the Federal Register.

    The Catalog of Federal Domestic Assistance Number for this 
program is 81.049 and the solicitation control number is ERFAP 10 
CFR Part 605.

    Issued in Washington, DC on November 15, 2002.
John Rodney Clark,
Associate Director of Science for Resource Management.
[FR Doc. 02-29751 Filed 11-21-02; 8:45 am]
BILLING CODE 6450-01-P