The investigators in this program are Dr. Ramesh Ganju, Dr. Xue-Feng Bai, Dr. Kenichi Tamama, Dr. Larry Lasky and Dr. Jian-Xin Gao. The individual areas of expertise include HIV and HCV/HIV co-infection (Ganju laboratory); mesenchymal stem cells (Tamama laboratory); autoimmunnity (Bai’s laboratory); bioengineering of hematopoietic cells (Lasky laboratory) and cancer immunotherapy (Gao’s laboratory). HIV and HCV/HIV Pathogenesis: Worldwide about 40 million people are infected with human immunodeficiency virus type 1 (HIV-1). The depletion of CD4+ T lymphocytes is a central pathogenic feature of (HIV-1) infection and is largely responsible for the profound immunodeficiency characteristic of the late stages of HIV disease. Dr. Ganju’s laboratory is analyzing the molecular mechanism of T-cell loss during HIV infection. They have shown that cross-talk between the chemokine receptor CXCR4/CCR5 and immune signaling components modulates the activities of novel apoptotic effector molecules. Dr. Ganju’s laboratory is further defining and elucidating HIV-induced apoptotic signaling mechanism in primary cells isolated from healthy and HIV-infected individuals, and determining how these signaling cascades could be altered to prevent the loss of immune cells during HIV infection. They are also exploring the effects of various molecules that block CXCR4 function on HIV pathogenesis. In this regard, they have shown that the novel Slit/Robo complex blocks CXCR4-mediated functional effects. Dr. Ganju’s laboratory is also elucidating the molecular mechanism of hepatic injury in HCV/HIV co-infection. Hepatitis C virus (HCV) infects approximately 40% of patients with human immunodeficiency virus (HIV). World wide about 200 million people are infected with HCV and about 40 million are infected with HIV. HCV/HIV co-infected patients have progressive liver disease that leads to cirrhosis and death. However, the molecular mechanism of enhanced cirrhosis and inflammation observed in these patients is not known yet. Dr Ganju’s laboratory observed that HCV and HIV envelope proteins induce apoptosis and inflammatory responses in hepatocytes via a novel “innocent bystander” mechanism. Further elucidation of signaling mechanisms revealed that the HCV/HIV envelope proteins cooperatively induce hepatocytic apoptosis by activating a novel downstream STAT1 signaling pathway. They are further elucidating the pathophysiology of liver disease caused by HCV/HIV co-infection that may help in the development of novel therapeutic strategies for HCV/HIV infection. Role of Mesenchymal stem cell in Regenerative medicine and Wound healing: Bone marrow mesenchymal stem cells (BMMSCs) are multipotent cells easily obtainable from adult human and expandable ex vivo, thus, these cells have a great potential for regenerative medicine and wound healing. Dr. Kenichi Tamama’s, who recently joined the Department, major long-term goal is to bioengineer blood vessels with BMMSCs and to promote wound healing process through enhancement of vascular support with BMMSCs. An area of current emphasis includes the study of differentiation of BMMSCs into smooth muscle cell (SMC) lineage in vitro. SMCs are the major components of hollow visceral organs including blood vessels. For tissue engineering and regeneration of these organs, an accessible autologous cell source for SMC would be ideal, however, SMCs obtained from adult tissues such as arteries are of little use because of the limited proliferation capacity of these cells in vitro and the invasiveness of the procedure itself. Our previous study showed that the inhibition of ERK-MAPK pathway drives BMMSCs into SMC lineage through up-regulation of myocardin, a very potent myogenic transcription factor. This data showed the potential of using BMMSCs as a source of SMCs for tissue engineering. Dr. Tamama is further analyzing the role of BMMSCs in wound healing process. These studies are being conducted in collaboration with Drs.Chandan Sen and Michael Miller of the Department of Surgery. Molecular mechanisms of autoimmunity: Dr. Bai’s laboratory has found a novel CD24-controled mechanism by which autoreactive T cells escape thymic deletion. Despite negative selection in the thymus, significant numbers of autoreactive T cells still escape to the periphery and cause autoimmune diseases when immune regulation goes awry. It is largely unknown how these T cells escape clonal deletion. Recently they found that CD24-deficiency caused deletion of autoreactive T cells that normally escape clonal deletion. Restoration of CD24 expression on T cells did not prevent autoreactive T cells from deletion. CD24-deficiency abrogated the development of experimental autoimmune encephalomyelitis in transgenic mice with a TCR specific for a pathogenic autoantigen. The role for CD24 in negative selection provides a novel explanation for its control of genetic susceptibility to autoimmune diseases in mice and humans. Dr. Bai’s laboratory has also found that Activation-Induced Cytidine Deaminase (AID) Mediates Tumor Evasion of Immunotherapy by Cytotoxic T Lymphocytes Activation induced cytidine deaminase (AID) is an enzyme essential for the generation of antibody diversity in B cells and is considered a general gene mutator. In addition, AID expression was implicated in the pathogenesis of human B cell malignancies, although the function of AID in cancer development is not understood. They have shown that siRNA silencing of AID in plasmocytoma dramatically increased its susceptibility to immunotherapy by cytotoxic T lymphocytes. Unexpectedly, AID knock-down did not reduce, but rather increased mutation rates in P1A and HPRT genes. Gene-array analysis show dramatic up-regulation of OX-2 (CD200) expression in AID-silenced J558 cells, which we show is responsible for the increased susceptibility to CTL therapy. Taken together, their data demonstrate a novel function of AID in tumor evasion of CTL therapy, at least in part by regulating expression of CD200. Biomedical Engineering of Hematopoietic cells: Dr. Lasky’s laboratory involves hematopoiesis and biomedical engineering in several aspects. They are involved in developing a modular 3D perfusion bioreactor system to produce hematopoietic and blood cells, currently emphasizing platelet production. They also are developing a silicon chip-based flow cytometry system, partially to monitor the output of their bioreactor modules. They are also are involved in genetic manipulations designed to influence self-renewal vs. differentiation in hematopoietic cells.