Full Text PA-95-087

METABOLIC ENGINEERING

NIH GUIDE, Volume 24, Number 32, September 1, 1995

PA NUMBER:  PA-95-087

P.T. 34

Keywords: 
  Metabolism 
  Genetics 
  Biology, Cellular 
  Enzymology 


National Institute of General Medical Sciences
National Institute of Diabetes and Digestive and Kidney Diseases

PURPOSE

The purpose of this program announcement (PA) is to encourage
research that will expand the conceptual and experimental basis of
metabolic engineering.  Basic research that contributes to a
quantitative understanding of the integration and control of genetic,
catalytic, and transport processes that comprise metabolism is
encouraged, as is research to create techniques that facilitate the
exploitation of metabolic processes for biomedical uses.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, eligible agencies of the Federal government.
Applications from minority individuals and women are particularly
encouraged.  Foreign institutions are not eligible to receive First
Independent Research Support and Transition (FIRST) awards (R29) or
program project grants (P01).

MECHANISM OF SUPPORT

Support of this research will be through the individual research
project grant (R01), program project grant (P01), FIRST Award (R29).
Potential applicants for program project grants are strongly urged to
contact the program staff listed under INQUIRIES for guidance
concerning both the organization and scope of the proposed work and
the preparation of the application itself.

RESEARCH OBJECTIVES

The study of intermediary and secondary metabolism at one time was
the centerpiece of biochemistry and cellular physiology.  This
endeavor provided one of the first examples that cellular processes
could be understood in molecular terms; it also brought into sharp
relief the importance of enzymes as critical mediators of cellular
activities.  Despite the successes of decades of investigations of
cellular metabolism, there still appears to be a vast amount to be
learned about metabolism.  While it is true that the enzymological
sequences and intermediates of many metabolic pathways in a small
number of well-studied organisms are known with some confidence,
little is known in quantitative terms of the controls and integration
of these pathways.  Hence, it is difficult to predict rigorously the
responses of metabolism to environmental changes and shifts in
developmental programs.  Investigations of these facets of
intermediary and secondary metabolism are hampered by an inability to
examine intracellular metabolite concentrations and enzyme activities
in vivo, and by a lack of adequate analytical models to organize and
describe the data.

It is also clear that there is limited knowledge of the range of
extant metabolic potential.  There are vast numbers of organisms that
have never been examined metabolically; some of these, such as the
archaebacteria, various anaerobic bacteria, and marine microbes may
utilize metabolic systems that are biochemically fascinating and
potentially useful.

An emerging approach to the understanding and exploitation of
metabolic processes is metabolic (or pathway) engineering.  As the
name implies, metabolic engineering is the targeted and purposeful
manipulation of the pathways of an organism.  Metabolic engineering
typically involves the alteration of cellular activities by the
manipulation of the enzymatic, transport, and regulatory functions of
the cell through the use of recombinant DNA and other genetic
techniques.  Much of this effort has focussed on microbial organisms,
but important work is being done in plants, and cultured cells from
both plants and animals.

The prospects for successful metabolic engineering can be seen in two
areas.  On the one hand, it can be used to create a microbial or
plant-based production route for useful quantities of "small"
molecules, such as amino acids and other nutritionally important
molecules, antineoplastics, various antibiotics (or their
derivatives) and other valuable secondary metabolites.  On the other
hand, metabolic engineering can also provide a route to targeted
metabolic changes useful in the exploration of the control
architecture that integrates the genetic and catalytic processes in
both normal and aberrant cells.  While this latter approach is widely
used already in contemporary cell biology, the systems-oriented,
quantitative tools of metabolic engineering could provide access to
an understanding of metabolic pathways that is significantly more
amenable to mathematical analysis and modelling.

The purpose of this program announcement is to promote investigations
into the nature of metabolism, its control and its biomedically
useful exploitation.  Through this program announcement the National
Institute of General Medical Sciences (NIGMS) is encouraging the
submission of applications for grants to support research into such
topics as the following:

o  the control mechanisms and the determinants of flux for pathways
where these factors are not well understood;

o  the development and application of analytical instrumentation and
techniques to study quantitatively the in vivo behavior of metabolic
enzymes and regulatory molecules;

o  the identification of additional genetic tools, e.g., selective
markers, reporter genes, vectors, and regulatory molecules for the
introduction of targeted synthetic or regulatory capacity into host
cells;

o  the creation of a broader range of host cells for the introduction
of heterologous genes;

o  the enhancement of techniques for maintaining the viability and
genetic stability of engineered cells;

o  databases and computational tools for pathway analysis that would
facilitate quantitative modelling of metabolism;

o  the development of an improved understanding of the determinants
of small molecule transport;

o  the exploration of systems showing potentially novel metabolic
capacities, such as plants and diverse microbes.

This listing is not meant to be all-inclusive.  There are, no doubt,
many areas of research, not specified above, that could contribute to
both an expanded understanding of metabolic processes and a
substantial broadening of their utilization for biomedical ends.

It is expected that some of the research projects proposed in these
areas would rely on collaboration between investigators from
different disciplines -- biochemistry and chemical engineering, for
example.  Such collaborations, where two or more approaches can
enhance the likelihood of success, would be welcome, but are not
required.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.  Application kits are
available at most institutional offices of sponsored research and may
be obtained from the Office of Grants Information, Division of
Research Grants, National Institutes of Health, 6701 Rockledge Drive,
Room 3032, MSC 7762, Bethesda, MD 20892, telephone (301) 710-0267.

The title and number of this program announcement must be typed in
Section 2 on the face page of the application (i.e., "Metabolic
Engineering," PA-95-).

For investigators applying for support through the FIRST Award
mechanism (R29), three letters of reference must be submitted with
the application attached to the face page.  FIRST (R29) award
applications submitted without the required number of reference
letters will be considered incomplete and will be returned without
review.  An applicant submitting a revised application in response to
this program announcement must again submit reference letters.

The completed original application and five legible copies must be
sent or delivered to:

OFFICE OF GRANTS INFORMATION
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS
referral guidelines.  Applications that are complete will be
evaluated for scientific and technical merit by an appropriate peer
review group convened in accordance with the standard NIH peer review
procedures.  As part of the initial merit review, all applications
will receive a written critique and undergo a process in which only
those applications deemed to have the highest scientific merit,
generally the top half of applications under review, will be
discussed, assigned a priority score, and receive a second level
review by the appropriate national advisory council or board.

Review Criteria

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the proposed budget and duration in relation to
the proposed research;

o  adequacy of plans to include both sexes and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.

The initial review group will also examine the provisions for the
protection of human and animal subjects, the safety of the research
environment, and conformance with the NIH Guidelines for the
Inclusion of Women and Minorities as Subjects in Clinical Research.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications.  The following will be considered in making funding
decisions:

o  quality of the proposed project as determined by peer review;
o  availability of funds;
o  program priority of research in the area of the program
announcement and other areas of Institute or Center interest.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Warren Jones, Ph.D.
Division of Pharmacology, Physiology, and Biological Chemistry
National Institute of General Medical Sciences
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-5938
FAX:  (301) 480-2802
Email:  JONESW@gm1.nigms.nih.gov

James Anderson, Ph.D.
Division of Genetics and Developmental Biology
National Institute of General Medical Sciences
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-0943
FAX:  (301) 480-2228
Email:  ANDERSOJ@gm1.nigms.nih.gov

Catherine McKeon, Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 5AN-18B
45 Center Drive, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8810
FAX:  (301) 480-3503
Email:  McKeonC@ep.niddk.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Ruth Monaghan
Grants Management Office
National Institute of General Medical Sciences
45 Center Drive, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-5135
FAX:  (301) 594-2554
Email:  MONAGHAR@gm1.nigms.nih.gov

Ms. Donna Huggins
Grants Management Branch
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 6AN-49K
45 Center Drive, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8848
FAX:  (301) 480-3504
Email:  HugginsD@ep.niddk.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance Numbers 93.821, 93.847, 93.859, and 93.862.  Awards are
made under authorization of the Public Health Service Act, Title IV,
Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC
285c-8 and 285k) and administered under PHS grants policies and
Federal Regulations 42 CFR 52 and 45 CFR Part 74.  This program is
not subject to the intergovernmental review requirements of Executive
Order 12372 or Health Systems Agency review.

The PHS strongly encourages all grant and contract recipients to
provide a smoke-free workplace and promote the non-use of all tobacco
products.  In addition, Public Law 103-227, the Pro-Children Act of
1994, prohibits smoking in certain facilities (or in some cases, any
portion of a facility) in which regular or routine education,
library, day care, health care or early childhood development
services are provided to children.  This is consistent with the PHS
mission to protect and advance the physical and mental health of the
American people.

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