I am currently a research fellow in Dr. David Scadden's laboratory at The Center for Regenerative Medicine and Massachusetts General Hospital (MGH). I have completed the clinical requirements of my fellowship in transfusion medicine in the Harvard-wide program. My education as a physician scientist has focused on developing clinical expertise in hematology/oncology and clinical pathology/ transfusion medicine and basic research training on the study of leukemia. I am applying for a Mentored Clinical Scientist Development Award (K08) in order to have protected time to acquire additional scientific training in stem cell biology and in-vivo microscopy and to prepare for a career as an independent researcher. My long-term career goal is to establish a career as an independent physician scientist at a major academic institution dedicating at least 75% of my time to basic research and 25% of my time to clinical work and teaching in a blood transfusion and/or coagulation service. The Scadden Laboratory is an ideal choice for my training and eventual path to scientific independence, as Dr. Scadden, who is an excellent mentor, is known worldwide for his work in hematopoietic stem cell biology and the bone marrow microenvironmental niche. He has an excellent track record of training young scientists. The Center of Regenerative Medicine is a very collaborative environment providing me with immediate access to well-known and well-established research investigators who are applying cutting-edge technologies and model organisms highly relevant to many different areas of biology, including stem cell and cancer biology and cancer genetics. In addition I can make use of all the resources available to me at The MGH Center for Regenerative Medicine, Harvard Medical School, Massachusetts General Hospital, The Harvard Stem Cell Institute and within the Scadden Laboratory. I am very fortunate to have an advisory committee consisting of Dr. Scadden, Dr. Van Etten, Chief of Hematology/Oncology at Tufts Medical Center and a leading expert in CML and other myeloproliferative disorders, and Dr. Charles Lin, Associate Professor at the Wellman Center for Photomedicine. I will formally and regularly meet with my mentor and my advisors individually and in four- way meetings. I will also be able to benefit greatly from my advisors'contacts to other scientists in their respective fields As part of my scientific training I will pursue formal graduate level coursework in ethics, statistics and stem cell biology through the Harvard Medical School Division of Medical Sciences. In addition, I will attend the weekly lab meetings of our laboratory, floor meetings with members of the Center for Regenerative Medicine and the Cancer Center, seminars at the Center for Regenerative Medicine and the other academic institutions in Boston. I plan to attend two scientific meetings per year. I received training in the responsible conduct of research through the Partners Healthcare Program in the Responsible Conduct of Research. I will continue to teach 4 lectures to blood bank/coagulation residents at MGH and I plan to do a limited amount of clinical work by signing out coagulation cases at MGH and attending in the MGH blood bank. I have chosen to focus my research on analyzing the LSC niche in chronic myeloid leukemia (CML), as understanding of the biology of the LSC niche and, ultimately, the development of strategies to manipulate this niche will improve current and future treatment strategies for leukemia. This is important, as tyrosine kinase inhibitors (TKIs) have limited efficacy targeting leukemic stem cells (LSCs) despite now being the treatment of choice for CML. It is believed that the LSC niche provides a """"""""sanctuary"""""""" for LSC where they are protected from the cytostatic effects of therapy. Lack of eradication of the LSC can lead to progression of CML to the blastic phase which closely resembles an acute leukemia. Targeting the LSC and LSC-niche interactions, therefore, is an important and novel goal in the treatment of CML and builds on my prior work in Dr. Van Etten's laboratory, where we first defined the interactions of the LSC with its bone marrow microenvironment. Preliminary functional experiments in the murine transduction/transplantation model of CML and B-cell acute lymphoblastic leukemia (B-ALL) in Dr. Scadden's laboratory demonstrate that niche modification can affect leukemic outcome. Furthermore, interaction of CML cells with their niche alters niche components like osteoblasts. The goals of my proposal therefore are: * To determine the microanatomy of the BM (BM) microenvironment in CML. * To test how leukemic cells and osteoblasts mutually interact with each other. * To test whether pharmacological treatment can alter the microanatomy of the leukemic stem cell niche and alter the malignant phenotype. In summary, the proposed research and training activities constitute a comprehensive program which will allow me to grow as a scientist and transition to a career as an independent researcher. Simultaneously, I hope to discover ways to influence the malignant phenotype of the leukemia and means to target the LSC in its niche, in order to, ultimately, add to the improvement of therapy for this intractable disease.
A cure of chronic myeloid leukemia (CML), one of the leukemias with the highest prevalence, is impeded by the resistance of the leukemic stem cell to imatinib, the drug of choice for this disease. It is hypothesized that the leukemic stem cells reside in a """"""""sanctuary"""""""" within the bone marrow, where the leukemic cells are produced. The goals of this project are to define the microanatomy of this niche by use of in-vivo microscopy and a mouse model of CML, to manipulate the bone cells, the osteoblasts, which are constituents of this niche and to define strategies by which to dislocate the leukemic stem cells from their """"""""sanctuary"""""""", in order to render them more sensitive to therapy with imatinib.
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