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Michael A. Farrar, Ph.D.
Associate Professor
Department of Laboratory Medicine and Pathology
Washington University, 1993, Ph.D.
farra005@umn.edu
612-625-0401 office
612-625-3608 lab
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Research Interests:
Signal transduction and lymphocyte development
Research in my lab explores how signal transduction pathways
regulate lymphocyte development and activation. Lymphocytes
develop from hematopoietic stem cells and go through characteristic
stages of differentiation that results in the formation of
functional, mature T or B cells. These stages are carefully
regulated by the action of growth factor and cytokine receptors,
as well as the clonotypic T cell and B cell antigen receptors.
A key question is how signaling pathways downstream of these
receptors regulate various aspects of B and T cell maturation.
Current efforts in the lab seek to elucidate how two such
pathways, the Ras and Jak/STAT signaling cascades, entrain
these developmental processes. This is being done using a
variety of techniques, including retroviral expression strategies
and the use of mice expressing dominant negative and activated
Ras, Raf and STAT transgenes, in concert with subtractive
cDNA libraries and gene microarray technology. Using these
approaches we have recently discovered that activation of
the transcription factor STAT5 is sufficient to rescue B cell,
but not T cell, development in interleukin-7-receptor deficient
mice. In addition, we also have evidence that the STAT5 pathway
may play an important role in the process that regulates whether
a hematopoeitic stem cell will develop into a B or T cell
(lineage commitment). To more precisely identify STAT5 gene
targets involved in these processes, we have developed a novel,
chemical-induced dimerization approach that allows us to selectively
activate the STAT5 signaling pathway in the absence of confounding
signals from other signal transduction pathways. Using this
approach, we hope to identify novel STAT5 targets, in both
developing B and T cells, that regulate lymphocyte development
and lineage commitment.
The other major question we seek to address is how distinct
signaling pathways govern lymphocyte activation. For example,
we have recently discovered a role for STAT5 signaling in
the development of regulatory T cells (Tregs). Tregs are required
to prevent autoimmunity; mice and humans which lack Tregs
develop multiple autoimmune syndromes. We have demonstrated
that mice which lack STAT5 also fail to develop Tregs. Conversely,
constitutive activation of STAT5 in Tregs leads to a large
increase in this cell type. We are currently studying the
molecular mechanisms by which STAT5 alters Treg development
and function. In addition, we seek to determine whether Tregs
with enhanced STAT5 signaling act as more efficient suppressors
of autoimmune disorders such as diabetes, systemic lupus erythematosis,
or inflammatory bowel disease.
Selected Recent Publications:
- M.A. Farrar, J. Alberola-Ila, and R.M. Perlmutter. Direct
activation of the Raf-l kinase cascade via coumermycin-induced
dimerization. Nature
383, 178-181, 1996.
- B.M. Iritani, K.A. Forbush, M.A. Farrar, and R.M. Perlmutter.
Control of B Cell Development by Ras-mediated Activation
of Raf. EMBO
J. 16: 7019-7031, 1997.
- M.A. Farrar, S.H. Olson, R.M. Perlmutter. Coumermycin-induced
GyrB-containing fusion proteins. Methods in Enzymology.
327: 421-429, 2000.
- M. Prlic, B. Blazar, M. A. Farrar, A. Ma, and S. C. Jameson.
In Vivo Survival and Homeostatic Proliferation of Mature
NK Cells. J.
Exp. Med. 197: 967-976, 2003.
- M.A. Burchill, C.A. Goetz, M. Prlic, J.J. O’Neil,
I.R. Harmon, S.J. Bensinger, L.A. Turka, P. Brennan, S.C.
Jameson, and Michael A. Farrar. Distinct Effects of STAT5
Activation on CD4+ and CD8+ T Cell Homeostasis: Development
of CD4+CD25+ Regulatory T Cells Versus CD8+ Memory T Cells.
J.
Immunol. 171: 5853-5864, 2003.
- C.A. Goetz, I.R. Harmon, J.J. O’Neil, M.A. Burchill,
and M.A. Farrar. STAT5 Activation Underlies Interleukin-7-dependent
B Cell but not T Cell Development.
J Immunol. Apr 15;172(8):4770-8, 2004.
Last modified on: January 30, 2006 |
