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

Cell death plays an essential role in metazoan homeostasis.  Members of the tumor necrosis factor (TNF) and TNF receptor (TNFR) family are crucial regulators of cell death.  Our lab is interested in how cell death contributes to the induction of immune responses.  One of the ways by which cell death can modulate immune responses is through the induction of programmed necrosis.  Necrotic cell death is distinguished from apoptosis by extensive cell and organelle swelling, the early rupture of plasma membrane, and the lack of caspase activation.   The release of endogenous cellular adjuvants can cause inflammation and stimulate immune responses.   Our long-term goal is to understand the biochemical regulation of programmed necrosis and the role programmed necrosis plays in inflammation, virus infections, autoimmune diseases and cancers.

Current projects:

1. Molecular regulation of programmed necrosis

Using RNA interference, we have recently identified several kinases including RIP1 and RIP3 that critically regulate programmed necrosis.  We show that a pro-necrotic signaling complex containing RIP1 and RIP3 are critically required for the induction of programmed necrosis.  We are currently investigating how the assembly of this RIP1-RIP3 complex is regulated.  Moreover, we are interested in identifying the downstream substrates for the RIP1-RIP3 kinase complex, and the effector mechanism that causes necrotic cell injury.

2. Programmed necrosis in anti-viral immunity

One of the physiological situations in which necrosis plays an important role is during viral infections.  Using vaccinia virus infections in mice as models, we have demonstrated a critical role for RIP3-dependent programmed necrosis in virus-induced inflammation and innate immune responses.  We are currently examining whether programmed necrosis and the subsequent inflammation it causes may also impact the induction of adaptive immune responses.  In addition, we are evaluating the role of programmed necrosis in other virus infections. 

3. How do viruses inhibit host cell death?

Inhibition of host cell death is widely touted as an immune evasion strategy employed by viruses.  In support of this hypothesis, many viruses encode inhibitors against the host cell death machinery.  We have recently identified several classes of viral inhibitors that potently inhibits programmed necrosis.   One of the challenges in the future will be to identify the molecular mechanisms by which viral inhibitors modulate the pro-necrotic signaling pathway.

4. Regulation of TRAIL signaling in immune cells

TRAIL (TNF-related apoptosis inducing ligand) is a TNF-like cytokine with potent cytotoxicity against many tumor cells, but are generally non-toxic to normal cells.  Of the five identified TRAIL receptors, two are termed “decoys” due to their ability to negatively regulate the apoptotic function of other TRAIL receptors.  We have found that signaling by TRAIL is in part regulated at the level of assembly of “pre-ligand complexes” between death receptors and the decoy receptors.  Current and future efforts will focus on understanding how the assembly of different TRAIL receptor complexes regulates death and non-death signaling in immune cells and cancer cells.

Selected publications:

1. Y. Cho, S. Challa, D. Moquin, R. Genga, T.D. Ray, M. Guildford and F.K.M. Chan .  Phosphorylation-Driven Assembly of RIP1-RIP3 Complex Regulates Programmed Necrosis and Virus-Induced Inflammation.  Cell 137: 1112-1123 (2009). Pubmed Link

2. F. K. Chan .  Three is Better Than One: Pre-ligand Assembly in the Regulation of TNF Receptor Signaling.  Cytokine 37(2): 101-107 (2007). Pubmed Link

3. M. Woelfel, J. Bixby, M.A. Brehm and F. K-M. Chan .  Transgenic expression of the viral FLIP MC159 causes lpr/gld-like lymphoproliferation and autoimmunity.  J. Immunol. 177: 3814-3820 (2006). Pubmed Link

4. L.M. Sedger, S.R. Osvath, G. Li, X-M, Xu, F.K-M. Chan , J.W. Barrett and G. McFadden.  Poxvirus TNF-R like T2 proteins contain a conserved pre-ligand assembly domain (PLAD) that inhibits cellular TNF-R1 induced cell death.  J. Virol. 80(18): 9300-9309 (2006). Pubmed Link

5. L. Zheng, N. Bidere, D. Staudt, A. Cubre, J. Orenstein, F.K. Chan and M. Lenardo.  Competitive control of independent programs of tumor necrosis factor-induced cell death by TRADD and RIP1.  Mol. Cell. Biol., 26(9): 3505-3513 (2006). Pubmed Link

6. L. Clancy, K. Mruk, K. Archer, M. Woelfel, J. Mongkolsapaya, G. Screaton, M. J. Lenardo and F. K. M. Chan.   PLAD-mediated ligand-independent association between TRAIL receptor 4 and TRAIL receptor 2 regulates TRAIL-induced apoptosis.  Proc. Natl. Acad. Sci., 102(50): 18099-18104 (2005). Pubmed Link

7. G-M. Deng, L. Zheng, F. K. M. Chan and M. J. Lenardo.  Amelioration of inflammatory arthritis by targeting the Pre-ligand assembly domain (PLAD) of tumor necrosis factor receptors.  Nat. Med. 11(10): 1066-1072 (2005). Pubmed Link

8. F. K. M. Chan, J. Shisler, L. Zheng, J. G. Bixby, M. Felices, J. Orenstein, B. Moss and M. J. Lenardo. A Role for Tumor Necrosis Factor Receptor 2 (TNFR-2) and Receptor-interacting Protein (RIP) in Programmed Necrosis and Anti-Viral Responses.  J. Biol. Chem., 278(51): 51613-51621 (2003). Pubmed Link

9. F.K.M. Chan , H. J. Chun, L. Zheng, R. M. Siegel, K. L. Bui and M. J. Lenardo.  A Novel Domain in Tumor Necrosis Factor Receptors Mediates Pre-Ligand Receptor Assembly and Signaling.  Science, 288:2351-4 (2000). Pubmed Link

Potential Rotation Projects

1. Examining TRAIL-induced apoptosis in cancer and normal cells.
   We have found that primary CD8+ T-cells are resistant to while most of the cancer cells are sensitive to TRAIL-induced apoptosis.  However, we recently found that certain stimulation to the cells can reverse the cellular sensitivity to TRAIL.  In this rotation project, the student will examine the molecular signals that control cellular sensitivity to TRAIL-induced apoptosis.  Specifically, the students will examine the role of lipid rafts and protein kinase C in regulating TRAIL response.  The student will learn standard biochemical and molecular biology techniques in this project.  In addition, the student will be exposed to concepts relating to receptor signal transduction, cell death and TNF receptor biology.   
   
   
2. Molecular regulation of programmed necrosis.
   TNF stimulation through TNF receptors activates a myriad of biological responses ranging from cell death to inflammation.   Interestingly, apoptosis is a dominant cell death pathway over programmed necrosis.  Thus, inhibition of caspases, which is an essential step during apoptosis, is crucial for the induction of programmed necrosis.  In this rotation project, the student will examine the signals that control the induction of apoptosis versus programmed necrosis.  Specifically, the student will examine the role of several TNF receptor signaling molecules such as caspase-8, RIP and TRAF2 in this process.  The students will learn about cell death and TNF receptor biology in this project.   
   
   
3. TNF-induced programmed necrosis in viral infections.
   We have identified several viral proteins termed vFLIPs that are potent inhibitors of TNF-indcued apoptosis and programmed necrosis.  This finding strongly suggests that apoptosis and programmed necrosis play central role in host defense against viral infections.  In this rotation project, the student will examine transgenic mice that express a potent cell death inhibitor for their immune response to viral infections.  The student will learn different immunological techniques and concepts in this rotation project.

Academic Background

Education:

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.