Walter J. Esselman, Ph.D.

esselman@msu.edu

Research

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.