Section: Research

Postdoctoral Position Available

Francis Chan, Ph.D.

Academic Role: Assistant Professor

Faculty Appointment(s) In:
   Pathology

Other Affiliation(s):
   Center for AIDS Research
   Interdisciplinary Graduate Program
   Program in Immunology and Virology

The Role of Programmed Cell Death in Immune Functions and Diseases

One of the hallmarks of the immune system is the constant expansion and contraction of different cell populations as a result of homeostatic immune regulation. Expansion and proliferation of T and B lymphocytes and antigen-presenting cells (APCs) in the midst of antigenic challenges is countered by contraction of the same populations of cells through apoptosis as the immune reaction attenuates. Hence, apoptosis or programmed cell death is at the heart of homeostatic balance within the immune system. Members of the tumor necrosis factor (TNF) receptor superfamily play critical roles in lymphocyte apoptosis and homeostatic regulation within the immune system. The long term goal of the lab is to use a variety of biochemical, biophysical and genetic approaches to delineate the mechanisms by which various TNF receptor-like molecules regulate immune functions and development. Current projects include:

1. Regulation of TNF-Related Apoptosis-Inducing Ligand (TRAIL)-mediated cytotoxicity in cancer and normal cells.
   TRAIL is a TNF-like cytokine with potent cytotoxicity against tumor cells, but not normal cells. TRAIL binds to multiple receptors on the cell surface.  Two of these receptors do not have an intact cytoplasmic death domain and were often referred to as "decoy receptors".  We recently identified a domain in the extracellular region of one of the decoy receptors, termed PLAD (for pre-ligand assembly domain), that mediates association with the death-inducing TRAIL receptors prior to ligand binding.  Surprisingly, this pre-ligand interaction, but not ligand binding by the decoy receptor, is essential for protection against TRAIL-induced apoptosis.  Using biochemical and biophysical techniques such as fluorescence resonance energy transfer (FRET), we are currently examining whether this pre-ligand interaction may explain the preferential cytotoxicity of TRAIL towards tumor cells, but not normal cells. 
   
   
2. Molecular regulation of TNF-induced programmed necrosis.
   We and other groups have recently identified a morphologically distinct form of programmed cell death that we have termed "programmed necrosis".  Like apoptosis, programmed necrosis can be induced by stimulation with death cytokines such as TNF, TRAIL and FasL.  However, unlike apoptosis, our work has demonstrated that programmed necrosis occurs in the absence of caspase activation, but does require the protein kinase RIP.  In fact, inhibition of caspases stimulates the induction of programmed necrosis.  Our long-term interest is to elucidate the molecular pathway that regulates programmed necrosis. 
   
   
3. Elucidating the role of programmed necrosis in viral immunity. 
   We have identified several viral proteins termed vFLIPs (for viral FLICE/caspase-8-like inhibitory proteins) that are potent inhibitors of apoptosis and programmed necrosis.  This finding suggests that the two forms of programmed cell death play central role in viral immunity.  We are currently using animal models to evaluate the role of different cell death pathways in the control of viral infections.  Future plans include developing additional animal models that selectively interfere with different cell death pathway to examine their relative contribution to the control of viral infections. 
   

Office: S2 -125
Phone: 508-856-1664
Fax: 508-856-1665
E-mail: Francis.Chan@umassmed.edu
Keywords: Immunology, Cell Death, Cancer Biology, Autoimmunity, Viral Infections and Immunity

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Postdoctoral Position Available A postdoctoral position is available to study in this laboratory. Contact Dr. Chan for additional details.