Imaging cell homing and engraftment in the bone marrow

描述(由申请人提供)：这项建议的目标是为候选人在血液学和肿瘤学的学术研究生涯做准备。候选人是医学博士，博士学位是开发磁共振成像的受体靶向造影剂的癌症生物学博士学位。她最近完成了临床阶段的团契培训，目前正在马萨诸塞州总医院和哈佛医学院实验血液学和血液恶性肿瘤主任大卫·斯卡登博士的实验室接受进一步的研究培训。斯卡登博士是造血干细胞研究领域备受尊敬的领导者，在指导学员方面拥有丰富的经验。他的实验室将为候选人提供一个理想的环境，让他学习广泛的分子和细胞生物学技术，并进一步熟练地进行临床相关研究。此外，候选人将继续与威尔曼光医学实验室的Charles Lin博士合作，后者将提供分子成像方面的大量专业知识和资源。这些实验室和麻省理工学院癌症中心将为科学发展提供一个丰富的智力环境，有多种科学互动、教育研讨会、会议和期刊俱乐部的机会。 这项拟议的研究试图利用实时共聚焦和双光子荧光成像来确定白血病细胞在骨髓微环境中归巢和植入的机制。为了验证白血病细胞使用与良性白细胞相似的组织归巢机制的假设，拟议的实验将检查使白血病细胞和造血干细胞能够在非常特定的微环境中归宿和增殖的信号。这些机制的阐明可能最终为白血病治疗确定对正常造血毒性最小的新生物靶点。该方案的具体目的是：1)实现白血病细胞在小鼠骨髓中归巢和植入的实时成像；2)确定影响骨髓归巢的白血病-血管细胞黏附事件的分子基础；3)识别白血病和正常干细胞在体内骨髓归巢的区别，为治疗干预提供靶点。

DESCRIPTION (provided by applicant): The goal of this proposal is to prepare the candidate for an academic research career in Hematology and Oncology. The candidate is an M.D., Ph.D. who earned a doctoral degree in Cancer Biology developing receptor-targeted contrast agents for magnetic resonance imaging. She has recently completed the clinical phase of fellowship training, and is now pursuing further research training in the laboratory of Dr. David Scadden, director of Experimental Hematology and of Hematologic Malignancies at the Massachusetts General Hospital and Harvard Medical School. Dr. Scadden is a highly-regarded leader in hematopoietic stem cell research with extensive experience in mentoring trainees. His laboratory will provide an ideal environment for the candidate to learn a broad range of molecular and cellular biology techniques as well as gain further proficiency in the conduct of clinically relevant research. In addition, the candidate will continue a collaboration with Dr. Charles Lin of the Wellman Laboratories of Photomedicine, who will provide substantial expertise and resources in molecular imaging. These laboratories, and the MGH Cancer Center, will offer a rich intellectual environment ideal for scientific development, with multiple opportunities for scientific interaction, educational seminars, conferences and journal clubs. The proposed research seeks to define the mechanisms that govern leukemic cell homing and engraftment in the bone marrow microenvironment using real-time confocal and dual photon fluorescence imaging. To test the hypothesis that leukemic cells use tissue homing mechanisms analogous to those of their benign leukocyte counterparts, the proposed experiments will examine the signals that enable leukemic cells and hematopoietic stem cells to home to and proliferate within very specific microenvironments. Elucidation of these mechanisms could ultimately define new biologic targets for leukemia therapy that are minimally toxic to normal hematopoiesis. The specific aims of this proposal are: 1) to achieve real-time in vivo imaging of leukemic cell homing and engraftment in murine bone marrow, 2) to define the molecular basis of leukemic-vascular cell adhesion events that affect bone marrow homing, 3) to identify distinctions between leukemic and normal stem cell bone marrow homing in vivo that may provide targets for therapeutic intervention.