The role of Syndecan-2 in hematopoietic stem cell maintenance and regeneration

摘要 造血干细胞(HSCs)终生维持成人血液和免疫系统 有机体的。虽然造血干细胞移植在临床上用于白血病的根治治疗， 对于淋巴瘤和免疫紊乱，造血干细胞移植的成功程度差别很大，有些患者 由于造血干细胞植入效率低下，不得不接受多次移植。拟议项目的目标是 为了确定硫酸乙酰肝素蛋白多糖Syndecan-2如何调节HSC的维持和再生。 目的1将利用新产生的组织特异性基因敲除小鼠来分析Syndecan-2在 调节HSC的植入，同时进行Syndecan分子基序的结构-功能分析- 2介导嫁接和生态位再生。目标2将分析Syndecan-2在调节 放射损伤和骨髓抑制联合应用于HSC体内模型的应激恢复 自我更新。这些实验将证明Syndecan-2在介导HSCs维持和 再生，为进一步研究蛋白多糖如何调控造血干细胞提供了基础知识。 从完成拟议目标中获得的知识可望具有广泛的潜力。 对接受化疗和放射治疗的患者的贡献，作为其治疗方案的一部分 癌症、免疫疾病、白血病和贫血的种类及公共卫生的治疗价值 治疗遭受意外辐射的患者的立场。 我的职业目标是成为一家顶级学术研究机构的助理教授。我瞄准了 领导一个研究项目，研究蛋白多糖如何调节HSC和HSC微环境 在动态平衡和压力下。为了实现这些目标，拟议的项目在 模拟HSC损伤后的恢复，同时扩展我对糖生物学和生长因子信号转导的知识。 根据这个奖项，我将在加州大学洛杉矶分校约翰·丘特博士的指导下进行拟议的培训，他已经 在HSC和生态位再生的转换建模方面有丰富的经验，并得到咨询的支持 拥有干细胞生物学、生长因子信号和蛋白多糖生物学专业知识的委员会。作为一名 博士后，我将在国际会议和我的指导委员会上介绍我的工作，这是 由该领域的专家组成。作为初级教员，我将接受实验室管理/领导力方面的培训， 写作、谈判和指导，帮助我领导一个成功的研究团队。拟议的项目将允许 在培养我在HSC生物学方面的技能的同时，我需要过渡到一个独立的研究职位。加州大学洛杉矶分校有 一流的研究设施、专业发展资源和行政支持，这将提供 作为一名博士后导师，支持我的研究和职业发展所需的基础设施 最终，我向独立的过渡。

ABSTRACT Hematopoietic stem cells (HSCs) maintain the adult blood and immune systems throughout the lifetime of an organism. While HSC transplants are used clinically for the curative treatment of patients with leukemias, lymphomas, and immune disorders, the success of HSC transplants varies considerably, with some patients having to undergo multiple transplants due to inefficient HSC engraftment. The goal of the proposed project is to identify how the heparan sulfate proteoglycan, Syndecan-2, regulates HSC maintenance and regeneration. Aim 1 will utilize newly generated tissue-specific knockout mice to analyze the contribution of Syndecan-2 in regulating HSC engraftment, while performing a structure-function analysis of the molecular motifs of Syndecan- 2 in mediating engraftment and niche regeneration. Aim 2 will analyze the role of Syndecan-2 in regulating hematopoietic recovery from stress by combining radiation injury and myelosuppression in vivo models of HSC self-renewal. These experiments will demonstrate the role of Syndecan-2 in mediating HSCs maintenance and regeneration, providing foundational knowledge to enable further study of how proteoglycans regulate HSCs. The knowledge procured from the completion of the proposed aims is expect to have broad potential contributions to patients undergoing chemotherapy and radiation therapy as a part of their treatment regimen for variety of cancers, immune diseases, leukemias and anemias and therapeutic value from a public health standpoint for treating patients that experience accidental radiation exposure. My career goals are to become an assistant professor at a top-tier academic research institution. I aim to lead a research program that investigates how proteoglycans regulate HSCs and the HSC microenvironment at homeostasis and during stress. To achieve these goals, the proposed project has embedded training in modeling HSC recovery from injury, while expanding my knowledge of glycobiology and growth factor signaling. Under this award, I will pursue the proposed training with the mentorship of Dr. John Chute (UCLA), who has substantial experience in translational modeling of HSC and niche regeneration, while supported by an Advisory Committee with expertise in stem cell biology, growth factor signaling and proteoglycan biology. As a postdoctoral fellow, I will present my work at international conferences and to my mentoring committee, which consists of experts in the field. As junior faculty, I will receive training in laboratory management/leadership, grant writing, negotiation, and mentoring to help me lead a successful research team. The proposed project will allow me to transition to an independent research position while developing my skillset in HSC biology. UCLA has superb research facilities, professional development resources and administrative support, which will provide the necessary infrastructure to support my research and career development as a mentored postdoctoral fellow and ultimately, my transition to independence.