The Role of GDF-15 in Organ Injury

Project: Research project

Description

DESCRIPTION (provided by applicant): This proposal seeks funding for the
scientific development of Leonidas Koniaris, M.D., an Assistant Professor of
Surgery at the University of Rochester School of Medicine. The candidate, a
gastrointestinal and trauma surgeon with over four years of basic science
research training in the function and signaling of cytokines and growth
factors, seeks funding for a mentored research program to examine the role of a
novel secreted factor, GDF-15, in shock and organ injury. Shock and organ
injury are common cytokine-dependent pathophysiologic processes that lead to
the morbidity and mortality seen in virtually all serious disease states. We
and others have cloned the new Transforming Growth Factor-B (TGF-B) superfamily
members GDF-15, and its human homologue GDF-l 4. GDF- 15 expression is potently
induced in mouse models of liver, bile duct, kidney and lung injury and shock.
Likewise, GDF-14 is highly expressed in acute and chronic human liver disease.
Macrophages from GDF-15 null mice hyper-express inflammatory cytokines and
chemokines both in the unstimuiated state and after treatment with phorbol
ester. Others report that GDF-14 can signal through the TGF-B receptor and
exert TGF-B-like anti-proliferative effects. Taken together these data suggest
that GDF- 14/15 is an early signal or mediator of shock and organ injury, that
GDF- 14/15 may limit the inflammatory response by regulating cytokine
production by macrophages, and that GDF 14/15 may regulate parenchymal cell
proliferation after tissue injury. This proposal seeks to determine the
function of GDF- 15 by describing its expression pattern, by evaluating the
response of GDF-15 null mice to organ injury and shock, and by examining the
effect of recombinant GDF-15 in vitro on macrophages and parenchymal cells and
in vivo in over-expressing mice. The candidate will be sponsored by the
Chairman of Surgery, James V. Silzmann, M.D., and Professor of Immunology I.
Nickolas Crispe, Ph.D., who will provide expertise and training in the areas of
murine surgery and shock and macrophage methodology respectively. The
completion of this mentored research training will further the candidate?s goal
of applying bench-derived scientific discovery to the treatment of surgical
disease as an independent investigator.
StatusFinished
Effective start/end date9/1/018/31/06

Funding

  • National Institutes of Health: $120,419.00
  • National Institutes of Health: $120,663.00
  • National Institutes of Health: $119,626.00
  • National Institutes of Health: $121,205.00
  • National Institutes of Health: $120,137.00

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Growth Differentiation Factor 15
Shock
Wounds and Injuries
Transforming Growth Factors
Macrophages
Cytokines
Growth Factor Receptors
Lung Injury
Allergy and Immunology
Bile Ducts
Research
Liver Diseases
Research Personnel
Medicine

ASJC

  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)