Dr. Walter J. Esselman, Professor of Microbiology and Molecular Genetics
Dr. Esselman is the Chair of the Department of Microbiology and Molecular Genetics. His primary teaching duty is to present immunology to the CHM and COM first year medical students.
Contact information:
Phone:
517-355-6463 ex 1510
email: esselman@msu.edu
Research Interests: For
a number of years the research effort in the lab has revolved around questions
involving the expression and function of protein tyrosine phosphatases (PTPs)
in the regulation of signaling, activation and transformation of T lymphocytes.
Our understanding of the mechanism of T lymphocyte activation is important
because these blood white cells are involved in the immune response to virtually
all types of infections, including those caused by viruses and bacteria. In addition, the T lymphocyte is involved in autoimmune conditions
such as arthritis, and in the inflammatory responses which lead to atherosclerosis
and diabetic retinopathy. Accordingly,
the work in the lab has been divided into basic studies of T lymphocyte activation
and into more translational research involving inflammatory cells in diabetic
retinopathy.
T lymphocyte activation. The specific aim of this study is to characterize
the expression and functional role of CD45 protein tyrosine phosphatase in lymphoid
cell proliferation and signaling. The tyrosine phosphatases (PTPs) are enzymes
which regulate the phosphorylation of signaling proteins that are essential
to the transduction of many types of signals received by the T lymphocyte. CD45 is a receptor-like transmembrane protein
containing a complex glycosylated external domain and a very large cytoplasmic
domain containing two PTP modules. The
external domain of CD45 undergoes alternative exon splicing which has been studied
in our laboratory by use of reverse transcription PCR. We are investigating the role of phosphorylation
of the cytoplasmic domain in the regulation of PTP activity. In addition,
the modulation of CD45 PTP activity has been studied under conditions of oxidative
stress in T lymphocytes. The detailed phosphorylation and oxidation of
CD45 in activated T cells has been determined by phosphopeptide mapping and
by MALDI-mass spectrometry. We are evaluating activation pathways
in T lymphocytes including NF-AT, MAPK and others. Ultimately, we plan
to precisely define the role of the tyrosine phosphatase domains in the function
of CD45. The understanding of phosphorylation and oxidation
of signaling molecules such as CD45 will contribute to an understanding of the
development of cancer as well as to the mechanisms of activation of immune cells.
Inflammation and
vascular endothelial cells. Recently the lab has focused on the role of
vascular inflammation in the progress of diabetic retinopathy. This project has been performed in close collaboration
with Dr. Julia Busik of the Physiology Department of MSU. Experiments have been performed with vascular
endothelial cells isolated from human retinas. The goal of the study is to define the mechanism
of microvascular damage initiated by pro-inflammatory substances and mediators.
The research has shown that exposure of human retinal vascular endothelial
(hRVE) cells to linoleic and arachidonic acids leads to the induction pro-inflammatory
adhesion molecules. The fatty acids
used are at levels comparable to those found in the blood of diabetic patients
(diabetic dyslipidemia). Once adhesion
molecules are expressed on the vascular cells, leukocytes from the blood attach
to the vessels and enter the retina where inflammation takes place. The overall result is damage to the retina
that is know as diabetic retinopathy. We
are now investigating the mechanism of adhesion molecules induction by fatty
acids and the difference in microvascular and macrovascular responsiveness that
could explain why certain organs are at greater risk for diabetic complications.
Selected
papers from the last few years:
Wang,
Y., W. Guo, L. Liang, and W. J. Esselman. 1999. Phosphorylation of CD45 by Casein
Kinase 2. Modulation of activity and mutational analysis. Journal of Biological Chemistry 274:7454-7461.
Wang,
Y., L. Liang and W. J. Esselman. 2000. Regulation of the Calcium/NF-AT T Cell
Activation Pathway by the D2 Domain of CD45. Journal of Immunology 164:2557-64.
Lee,
KyoungMun and Walter J. Esselman. 2001. cAMP
potentiates H2O2-induced ERK1/2 phosphorylation without the requirement for
MEK1/2 phosphorylation. Cell Signaling 13: 645-652.
Lee,
Kyoungmun and Walter J. Esselman. 2002. Inhibition of PTPs by H2O2 regulates
the activation of distinct MAPK pathways. Free
Radical Biology and Medicine. 33: 1121-32.
Wang,
Dongxia, Walter J. Esselman, Philip A. Cole. 2002.
Substrate conformational restriction and CD45-catalyzed dephosphorylation
of tail tyrosine-phosphorylated Src protein. Journal of Biological Chemistry
277:40428.
Lee,
Kyoungmun and Walter J. Esselman. 2003. Non-antioxidant properties of curcumin
inhibit STAT3 phosphorylation and c-Fos expression in Jurkat T lymphocytes. Submitted.
Chen,
Weiqin, Kathleen A. Gallo and Walter J. Esselman.
2003. Mixed lineage kinase-3
in T-cell activation: Role of protein kinase C in activation-mediated mixed
lineage kinase-3 hyperphosphorylation. Submitted.
Recent grants:
National
Institutes of Health, Regulation of CD45 phosphatase by phosphorylation.
02/01/98 to 06/30/03, about $135,000/year (direct). R01-AI/GM42794. P.I., W. Esselman. This grant was recently extendeded.
IRGP
#40768; W. Esselman (Co-PI), Julia Busik (Co-PI); 12/15/01–06/15/03, Michigan State University Research Initiation, $75,000 direct. Novel mechanisms for the development of diabetic retinopathy.
Elsa U. Pardee
Foundation; W. Esselman (PI), Kathy Gallo (Co-PI) 10/01/01 –01/31/03,
$60,000 direct. Proteolysis of
Mixed-Lineage Kinase 3 and Protein Kinase C-q in Cell Signaling
National Institutes of Health DK065014-01, 07/01/03-06/30/05, $200,000 direct, W. Esselman (Co-PI), Julia Busik (Co-PI); Dyslipidemia and retinal vascular endothelial cell dysfunction.