Natarajan Muthusamy DVM., PhD Associate Professor of Medicine CLL Research Laboratory Division of Hematology Dept. of Internal Medicine Natarajan Muthusamy DVM.,PhD: Hi, my lab is interested in transcriptional regulation of lymphocyte development and also...can I go back or restart this? Unknown: Yeah, you restart it. Natarajan Muthusamy DVM.,PhD: How do I restart this? Do I introduce myself as well? Unknown: Yeah, go ahead Natarajan Muthusamy DVM.,PhD: Hi, I'm Raj Muthusamy, I'm an associate professor in the Department of Medicine at the Ohio State University. My research is focusing on several aspects of B cell biology, as well as application of therapeutic targets in B cells. There are five major areas that I focus on. My research is involved in studying how lymphocytes develop. What are the transcriptional factors that influence the development of B and T lymphocytes is one of the major areas in the lab. I'm also interested in biological therapies in leukemia, in generating mouse models to study biological therapies directed against B cell malignancies. One of the major focus in the lab is to identify novel therapeutic targets, primarily focusing on phosphatases, as well as transcriptional factors. And finally, the major area that we have been recently venturing into is to develop therapeutic programs, which are directed towards targeted delivery of drugs. [Text on screen -Transcriptional Regulation of Lymphocyte Development -Biological Therapies in Leukemia -Mouse model creation-generic and disease specific -Small-molecule-targeted therapeutics -Targeted Delivery Program] Focusing on the transcriptional regulation of lymphocyte development and maturation. We develop animal models where we overexpress transgenes into specific cell types, for example, in B cells or T cells, and study the effect of overexpression of these transgenes in the development of lymphocytes. We also generate mouse models where we delete specific genes to understand how lack of expression of those genes are involved in development of lymphocytes in health and disease. We use multiple approaches: transgenic approach, gene-targeted approach in embryonic stem cells, gene knock-out mouse models, and knock-in mouse models. [Images on screen Image 1: Photo of transgenic models, Image 2: Photo of ES cell IVD model Image 3: Flow chart displaying complementation model Image 4: Photo of 2 mice with the label as "knock out models"] [Text on screen Transcriptional regulation of lymphocyte development and maturation] And also, apply complementation models for studying phenotypes that are evolving in animals where we don't have viable embryos. The primary focus on transcriptional regulation is revolving around two families of transcription factors: Ets family of transcription factor and CREB/ATF family of transcription factors. We have generated animal models that are either deficient in these transcription factors or with specific mutations that are exclusively expressed in the lymphoid lineages to study the lymphocyte development. [Flow chart illustrating the process of hematopoiesis (Stem cells becoming T cells, B cells, Myeloid, Red Blood Cells, Platelets, all specified)] One of the major focus in the lab is, in collaboration with Doctor John Byrd, is to study biological therapies in leukemia. We have been recently focusing on both lymphoid and myeloid leukemia. The focus on this research program is directed towards identifying novel target antigens on leukemia B cells, and engineering antibodies directed against such molecules, and applying them in vitro and in vivo therapeutic evaluations. [Text on screen Biological therapies in leukemia (Lymphoid and Myeloid leukemia): -Novel target identification and targeted therapeutics (CD37/LCP1) -Engineered Antibody therapeutics (CD33/CD37/BAFFR/CD20) -Mantle Cell Lymphoma focus (FTY720/CD74-milatuzumab0 CD37-Tetraspanin: -A therapeutic target in B cell malignancies] [Images on screen: Image 1: Photo of John C. Byrd, MD (Co-PI) Image 2: Photo of Rosa Lapokeebella, PhD Image 3: Photo of Franc Frissora Image 4: Photo of Kyle Beckwith] For evaluation of novel therapeutic antibody molecules, we need animal models, and that is one of the areas where there is a lot of requirement, a need for developing animal models. We have been involved in developing humanized animal models that also have leukemia, thus expressing a human target antigens on the leukemic cells. And we apply these mouse models to evaluate in vivo, in the context of the intact animal, in the context of the intact immune system, the therapeutic efficacy of these antibody molecules. [Text on screen Generation of mouse models for evaluation of human B cell-targeted therapeutics -Humanized CD37 and ROR1 Leukemia models -CD33 Tg mouse model (in progress) -Ets-Leukemia model and CREB Tg models -GVHD models] [Images on screen Image 1: Photo of Kyle Beckwith Image 2: Photo of Rajeswaran Mani Image 3: Photo of Yi-Cheng Mao Image 4: Frank Fissoraa] We also have been recently developing animal models to study myeloid leukemia, as well as graft versus host diseases. The third area of the research focus is targeted therapeutics. There are two areas that we are focusing on currently, targeting phosphatases as a potential therapeutics. In this case, we have recently developed a novel class of molecules called FTY720, derivatives of OSU-2S. And we have identified that these molecules activate phosphatases, and thereby resulting in cell death. Currently, we are also involved in developing small-molecule inhibitors for transcription factors that are involved in cell survival. One of the major recent collaborative projects with College of Pharmacy and College of Engineering involves targeted delivery of therapeutic molecules. These programs are focused on developing small-molecule formulations that are allowing us to deliver the drug of choice in a formulation that will deliver the drug to the selective cell type, in this case, particularly to the leukemic cells. We have developed the animal models that are relevant that will allow us to study these small molecules in a targeted formulation setting. The types of molecules that we have been evaluating using these target formulations include the phosphatase-directed therapeutics, as well as antisense RNAs, as well as micro RNAs. And these studies are primarily done by graduate students in the lab. And there are opportunities for further studies in this line of investigation. [Text on screen Targeted Delivery Program (Collaborative project with College of Pharmacy and Engineering) -Novel B cell-directed drug delivery -Mouse models for in vivo evaluation of targeted delivery. -RNA directed therapeutics (antisense ((G3139) and miRNA). -Targeted small molecules in CLL and MCL-FTY720/OSU-2S] [Images on screen Image 1: Photo of Frank Frissora Image 2: Chemical structure diagram of FTY720 (2-amino-2[2-(4-octylphenyl)ethyl]propane-1,3- diol) Image 3: Chemical structure diagram of OSU-2S ([(S0-2-amino-2-(4-[(6-methylheptyl)- oxy]phenethyl)pentan-1-ol])