2010 — 2012 |
Chow, Andrew |
F30Activity Code Description: Individual fellowships for predoctoral training which leads to the combined M.D./Ph.D. degrees. |
Maintenance of the Hematopoietic Stem Cell Niche Monocytes and Macrophages @ Icahn School of Medicine At Mount Sinai
DESCRIPTION (provided by applicant): Mobilization of hematopoietic stem and progenitor cells (HSPCs) into the peripheral blood has made harvest of donor cells for bone marrow (BM) transplantations more convenient and improved cell yield and engraftment. HSPC mobilization by G-CSF (Filgrastim) is mediated by modulation of the stem cell niche, which is the BM microenvironment that retains and regulates HSPCs. There have been many hints in the literature that monocytes and macrophages control the hematopoietic niche. This application proposes to study the role of the M-CSF receptor (CD115)-expressing cells in the maintenance of the HSC niche. Our preliminary data indicates that G-CSF reduces BM monocyte and macrophage numbers and in vivo depletion of these populations is correlated with HSPC mobilization and reduction in BM CXCL12, an HSPC retention chemokine. In this proposal, 1 will a) confirm this correlation in two additional in vivo models of CD115+ cell depletion, b) identify the factors mediating cross-talk (via microarray of CD115+ cells co-cultured with a murine BM-derived stromal cell line and protein array of culture supernatant), c) determine dependence of CDI 15-depletion-induced mobilization of HSPC on the sympathetic nervous system (using pharmacological, surgical and genetic models of sympathectomy), and d) elucidate synergy of this mobilization with other mobilizing agents (G-CSF and AMD3100). For aims a, c, d, e, I will assess HSPC mobilization by colony forming assays, CD115+ cell reduction by flow cytometry, and reduction in CXCL12 chemokine by ELISA. PUBLIC HEALTH RELEVANCE: While stem cell mobilization has made retrieval of donor cells for transplants more convenient and efficient, it yields an insufficient number of stem cells in up to 40% of patients. The experiments proposed can potentially lead to the development of new strategies targeting the BM monocytes and macrophages to maximize stem cell yield. The results of this project also has broad implications for the maintenance of non-hematopoietic stem cell niches, whose manipulation can be instrumental in facilitating tissue repair after injuries, such as myocardial infarction, traumatic burns, and neurodegeneration.
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1 |
2020 — 2021 |
Chow, Andrew |
K08Activity Code Description: To provide the opportunity for promising medical scientists with demonstrated aptitude to develop into independent investigators, or for faculty members to pursue research aspects of categorical areas applicable to the awarding unit, and aid in filling the academic faculty gap in these shortage areas within health profession's institutions of the country. |
Assessment of Tim-4+ Pleural Macrophages as Negative Regulators of Anti-Tumor T Cell Immunity in Lung Cancer @ Sloan-Kettering Inst Can Research
PROJECT SUMMARY/ABSTRACT Research: Lung cancer is the leading cause of cancer death in the United States. The success of immune checkpoint blockade (ICB) with antibodies to PD-(L)1 have been a remarkable clinical advance. However, the majority of patients do not respond to ICB monotherapy and most of those who initially do respond eventually succumb to the disease. Malignant pleural effusions represent a challenging clinical scenario that is associated with poor prognosis and reduced responses to ICB. Preliminary data presented in this proposal demonstrates that activated T cells surprisingly express phosphatidylserine despite remaining viable and cytotoxic. Moreover, this expression of phosphatidylserine mediates susceptibility to phagocytic clearance by peritoneal macrophages that express the phosphatidylserine receptor Tim-4. In addition, Tim-4 abrogation improves responses to ICB in a murine model of peritoneal carcinomatosis. As pleural macrophages are ontogenically and transcriptionally similar to their peritoneal macrophage counterpart, we hypothesize that Tim-4+ pleural macrophages impart immunosuppression in malignant pleural effusions by clearing anti-tumor CD8+ T cells. In this proposal, we will systematically characterize Tim-4+ macrophage-PShigh T cell interactions in both murine and human models of malignant pleural effusion. Furthermore, we will explore whether Tim-4 blockade has the potential to substantially enhance the efficacy of immunotherapy in lung cancer. Candidate: Dr. Andrew Chow is a Medical Oncology Fellow in the Department of Medicine at Memorial Sloan Kettering Cancer Center (MSKCC). He aims to become an independent, tenure-track physician-scientist investigating Tim-4+ pleural macrophages as a novel therapeutic target to overcome resistance to immunotherapies in lung cancer. Dr. Chow will conduct the proposed research under the mentorship of Drs. Charles Rudin and Jedd Wolchok, who are internationally recognized experts in lung cancer and immunotherapy, respectively. Dr. Chow has outlined a five-year period of mentored training that builds on his laboratory-based skills in mouse modeling, flow cytometry, and microscopy and his clinical training in medical oncology. For the next phase of mentored training, he will develop skills in single-cell RNA sequencing analysis, CAR T cell design and manufacture, CRISPR-Cas9 editing, and clinical protocol writing. Dr. Chow has also assembled a well- accomplished advisory committee composed of Drs. Sohrab Shah, Prasad Adusumilli, and Katherine Panageas, who will help to guide his training and research. Environment: MSKCC is the world's oldest and largest private cancer center, devoting more than 130 years to exceptional patient care, innovative research, and outstanding educational programs. MSKCC exposes trainees to an exceptionally robust academic research environment with a strong commitment and track record of successfully supporting junior faculty who are seeking careers as independent physician-scientists.
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