Infections and cancer are controlled by lymphocytes and innate immune cells in mammals. Cell survival, proliferative and cell death responses play critical role in proper function of the immune system. Patients with defects in cell death pathways develop lymphoproliferative diseases (lymphoid hypertrophy), recurrent infection, and predisposition to cancer. Therefore, understanding the molecular mechanism involved in the regulation of lymphocyte death responses will help develop effective therapeutic strategies for infectious diseases, autoimmune diseases, immunodeficiency and cancer.
Our research focuses on understanding the molecular mechanism involved in the regulation of the immune system through programmed cell death (PCD). Two major PCD pathways, apoptosis and necrosis are of particular interest because they play critical roles in immune cell development, responses to pathogens, inflammatory diseases, and cancer. Apoptosis is considered a benign form of PCD, occurs at various stages during lymphocyte development and responses, and is essential for eliminating non-functional, cancerous, or self-reactive lymphocytes. Dysregulation of lymphocyte apoptosis may cause autoimmune diseases, leukemia, and lymphoma. Necrosis has long been considered unregulated cell death which leads to cell rupture, resulting tissue damage. Recent evidence demonstrates that some forms of necrosis including necropotsis are tightly controlled cell death process. We are searching, by molecular cloning and by proteomic approaches, for proteins that are involved in cell death-signaling network. Physiological functions of each protein will be studied using various in vitro cell line systems, and using whole animals by transgenics and gene targeting (knockout) in mice. Our long-term goal is to identify key regulatory steps during cell death processes, that are potential targets for therapeutic intervention of various diseases. Current projects in our group are as follows.
A number of related receptors, designated “Death Receptors (DR)”, initiate a potent cell death signal upon engagement with cognate ligands. Fas is essential for apoptosis of self-reactive lymphocytes. Several years ago, we isolated a Fas-Associated Death Domain (FADD) protein, which is a mediator of apoptotic signal transduction in at least five death receptor pathways, Fas, Tumor Necrosis Factor Receptor I (TNFR-I), DR3, 4, and 5. By FADD gene knockout studies in mice, we found that FADD not only is essential for apoptosis, but plays a role in cell proliferation as well. Future studies are aimed at understanding the molecular mechanisms in signal switching by FADD, between two drastically distinct pathways: apoptosis and necrosis.
TRAIL-induced cancer cell death.
TRAIL is similar to Tumor Necrosis Factor (TNF), and induces apoptosis when binds to its receptors DR4 and 5. TRAIL is being vigorously studied because its cytotoxicity is restricted to tumor cells. Administration of recombinant TRAIL rejects tumor in mice with no obvious side effects. It is not fully understood how the selectivity of TRAIL-DR4/5-induced apoptosis is established. We are investigating whether the downstream FADD protein plays a regulatory role in this process. Indeed, FADD has been implicated to play a tumor suppressor role in certain genetic settings.
Other cell death molecules.
After membrane-proximal signaling, cell death is executed by a family of downstream killer proteases called Caspases. A number of proteins, such as FLIP, IAP, Bcl-2, and BID, regulate cell death by activating or suppressing Caspases, which are crucial in maintaining a normal physiology. We are investigating how the cell death protein network integrates various extracellular and intracellular signals in order to determine the fate of a cell.