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NIH Program Announcement - Metabolic Engineering

Anderson, James ANDERSOJ at gm1.nigms.nih.gov
Wed Apr 10 16:05:54 EST 1996

For those who might not have seen this announcement when it was first 
issued, here is a truncated version:


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

PA NUMBER:  PA-95-087

P.T. 34; K.W. 0765020, 1002019, 1002004, 0710055

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


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.


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).


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.


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

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

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 at 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 at 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 at ep.niddk.nih.gov

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