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Lymphocyte Cell Biology Unit |
Biography: Dr. Dan Longo received his M.D. degree with honors from the University of Missouri-Columbia in 1975. He trained in Internal Medicine at Harvard Medical School and Brigham and Women’s Hospital, in Medical Oncology at the National Cancer Institute (NCI), and did post-doctoral laboratory training in the Laboratory of Immunology, National Institute of Allergy and Infectious Diseases. He became a senior investigator at the NCI in 1980 and joined the NIA in 1995. | |
| Control of lymphocyte proliferation: Our initial interest in lymphocyte proliferation was stimulated by two factors; first, our clinical interest in the treatment of patients with lymphoma and second, the recognition that lymphocytes are terminally differentiated cells that nevertheless maintain the ability to proliferate. In most tissues, dividing cells are primitive precursor cells, not terminally differentiated functional effector cells. Lymphocytes are the only effector cells that retain the capacity to proliferate. However, the cells link their proliferative capacity either to recognition of specific antigenic determinants presented by antigen-presenting cells or to selective combinations of cytokine signals provided by other cells. Furthermore, the cells control their own proliferation and stop dividing after a period of time even in the setting of persistent exposure to antigens and/or cytokines. We wondered how lymphocytes stop their own proliferation and whether these mechanisms could be exploited and restored as a component of treatment of lymphoid malignancies. | |
| Physiological relevance of the mTOR pathway: Our initial interest in the mTOR pathway stemmed from the observation that the cyclosporin A-resistant CD28-mediated co-stimulatory pathway of T cell activation was sensitive to rapamycin, an mTOR-specific inhibitor. Rapamycin has been shown to block cell proliferation and induce anergy. The mTOR signaling pathway has been shown to coordinate two important processes during the cell cycle: mitochondrial bioenergetics and G1 phase cell cycle progression. Mitochondrial oxygen consumption and oxidative capacity have been shown to be regulated by the mTOR pathway. Mitochondria have been proposed to be the nexus for aging and calorie restriction. A better understanding of this pathway should shed light on the regulation of immune function and on the physiologic changes associated with aging. | |
Role of Hyperplasia Suppressor Gene (HSG) in cell growth: Our goal is to understand the mechanism of growth suppression by HSG. Our pervious data demonstrated that over-expression of HSG (later re-named mitofusin-2, Mfn2) exhibits a profound anti-proliferative and proapoptotic effects in vivo and in vitro. Currently, we are searching for target protein(s) with which HSG interacts, and trying to understand the mechanism of signal transduction underlying the growth suppression. | |
| Characterization of TGF-b signaling In B-cell lymphoma cells: One common feature of neoplastic cells is evasion of TGF-b1-mediated growth inhibitory effects. We have demonstrated earlier that promoter methylation of TGF-β receptor II (TβRII) resulting in the lack of expression of the receptor chain is one of the mechanisms of TGF-β resistance. Recently, we describe a novel tumor cell TGF-β-resistance mechanism: ligand-induced down-regulation of TβRII resulting in only transient TGF-β signaling. This form of TGF-β resistance proved to be reversible. Activated MEK binds to and stabilizes TGF-β receptor II and restores TGF-β signaling. Thus, an agent capable of activating MEK could restore TGF-β responsiveness to some cancers in vivo. Currently, we are investigating the mechanism of TβRII stabilization by MEK. | |
| Rapamycin-sensitive pathway of T cell activation: CD28-mediated costimulatory signal plays a pivotal role in the outcome of many immune responses including cytolytic responses in tumor and autoimmune diseases. Depending on the primary stimulation, CD28 can initiate multiple intracellular signaling pathways including a pathway that is insensitive to immunosuppressive drug, Cyclosporin A (CsA). This CsA- insensitive pathway is sensitive to immunosuppressive drug rapamycin, and believed to be involved in graft-vs-host disease (GVHD) during allogeneic bone marrow transplantation. Our current objectives focus on three areas: (1) characterization of the CsA-resistant rapamycin-sensitive pathway of T cell activation; (2) examination of the physiological significance of this pathway; and (3) the effect of aging on the rapamycin-sensitive pathway. | |
| PubMed: Search for listing of Dr. Longo's publications. | |
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Lymphocyte Cell Biology Unit |
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