Francis Ka Ming Chan PhD
|Institution||University of Massachusetts Medical School|
|Address||University of Massachusetts Medical School|
55 Lake Avenue North
Worcester MA 01655
|Institution||UMMS - Graduate School of Biomedical Sciences|
|Department||Immunology and Virology|
|Institution||UMMS - Graduate School of Biomedical Sciences|
|Department||Interdisciplinary Graduate Program|
|Institution||UMMS - Programs, Centers and Institutes|
|Department||Center for AIDS Research|
|1991||B.A.||University of California, San Diego (Summa Cum Laude)|
|1996||Ph.D.||University of California, Berkeley|
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.
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.
Figure 1: Electron micrograph of a vaccinia virus infected cell undergoing programmed necrosis. Note that the dying cell exhibits extensive intracellular vacuolation and mitochondrial swelling.
Figure 2: Electron micrograph of a necrotic cell exhibiting extensive loss of plasma membrane integrity.
Figure 3: A cartoon representation of how necrotic cell injury can trigger inflammation and stimulation immune responses during virus infections.
Potential Rotation Projects
- Examining TRAIL-induced apoptosis in cancer and normal cells.
We have found that primary CD8+ T-cellsare resistant towhile most of the cancer cells are sensitive to TRAIL-induced apoptosis. However, werecently 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 controlcellular 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 willbe exposed to concepts relating to receptor signal transduction, cell death and TNF receptor biology.
- Molecular regulation of programmed necrosis.
TNF stimulation through TNF receptors activates a myriad of biological responses ranging from cell death to inflammation. Interestingly, apoptosisis 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.
- 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.Inthis rotation project, the student will examinetransgenic 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.
A postdoctoral position is available
to study in this laboratory.
Contact Dr. Chan for additional details.
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