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

Syndecan-2 在造血干细胞维持和再生中的作用

• 批准号: 10696158
• 负责人: Christina Marie Termini
• 金额: $ 14.89万
• 依托单位: FRED HUTCHINSON CANCER CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10696158
• 关键词: Address; Adult; Advisory Committees; Anemia; Award; Biological Assay; Biology; Blood; Blood Vessels; Cell Count; Cell Maintenance; Cell Proliferation; Cells; Cellular biology; Chemotherapy and/or radiation; Clinical; Data; Dose; Endothelium; Engraftment; Equilibrium; Faculty; Glycobiology; Goals; Grant; Growth Factor; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Homeostasis; Human; Image; Immune System Diseases; Immune system; Immunodeficient Mouse; Individual; Infrastructure; Injury; Institution; Integral Membrane Protein; International; Knockout Mice; Knowledge; Laboratories; Lead; Leadership; Lymphoma; Malignant Neoplasms; Measures; Mediating; Mediation; Medical; Mentors; Mentorship; Microscopy; Modeling; Molecular; Molecular Analysis; Mus; Mutation; Myelosuppression; Natural regeneration; Organism; Pain; Patients; Phase; Polysaccharides; Positioning Attribute; Postdoctoral Fellow; Process; Proteoglycan; Public Health; Radiation Accidents; Radiation Injuries; Radiation exposure; Radiation therapy; Recovery; Regulation; Research; Resource Development; Role; Signal Transduction; Source; Stress; Structure; Surface; Testing; Therapeutic; Tissues; Training; Transplantation; Treatment Protocols; Umbilical Cord Blood; Work; Writing; Xenograft procedure; bone marrow failure syndrome; career; career development; cell growth; cell regeneration; curative treatments; differential expression; educational atmosphere; exhaustion; experience; experimental study; fibroglycan; genetic signature; hematopoietic stem cell niche; hematopoietic stem cell quiescence; hematopoietic stem cell self-renewal; hematopoietic tissue; improved; in vivo; in vivo Model; injury recovery; leukemia; mutant; post-doctoral training; preservation; professor; programs; radiation recovery; regeneration following injury; regenerative; repaired; research and development; research facility; self-renewal; skills; stem cell biology; stem cell engraftment; stem cells; success; symposium; transcriptome sequencing; translational applications; translational model; Address; Adult; Advisory Committees; Anemia; Award; Biological Assay; Biology; Blood; Blood Vessels; Cell Count; Cell Maintenance; Cell Proliferation; Cells; Cellular biology; Chemotherapy and/or radiation; Clinical; Data; Dose; Endothelium; Engraftment; Equilibrium; Faculty; Glycobiology; Goals; Grant; Growth Factor; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Heparan Sulfate Proteoglycan; Heparitin Sulfate; Homeostasis; Human; Image; Immune System Diseases; Immune system; Immunodeficient Mouse; Individual; Infrastructure; Injury; Institution; Integral Membrane Protein; International; Knockout Mice; Knowledge; Laboratories; Lead; Leadership; Lymphoma; Malignant Neoplasms; Measures; Mediating; Mediation; Medical; Mentors; Mentorship; Microscopy; Modeling; Molecular; Molecular Analysis; Mus; Mutation; Myelosuppression; Natural regeneration; Organism; Pain; Patients; Phase; Polysaccharides; Positioning Attribute; Postdoctoral Fellow; Process; Proteoglycan; Public Health; Radiation Accidents; Radiation Injuries; Radiation exposure; Radiation therapy; Recovery; Regulation; Research; Resource Development; Role; Signal Transduction; Source; Stress; Structure; Surface; Testing; Therapeutic; Tissues; Training; Transplantation; Treatment Protocols; Umbilical Cord Blood; Work; Writing; Xenograft procedure; bone marrow failure syndrome; career; career development; cell growth; cell regeneration; curative treatments; differential expression; educational atmosphere; exhaustion; experience; experimental study; fibroglycan; genetic signature; hematopoietic stem cell niche; hematopoietic stem cell quiescence; hematopoietic stem cell self-renewal; hematopoietic tissue; improved; in vivo; in vivo Model; injury recovery; leukemia; mutant; post-doctoral training; preservation; professor; programs; radiation recovery; regeneration following injury; regenerative; repaired; research and development; research facility; self-renewal; skills; stem cell biology; stem cell engraftment; stem cells; success; symposium; transcriptome sequencing; translational applications; translational model

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.

抽象的 造血干细胞（HSC）在一生中维持成人血液和免疫系统 有机体。虽然HSC移植在临床上用于治疗白血病患者，但 淋巴瘤和免疫疾病，HSC移植的成功差异很大，一些患者 由于HSC植入效率低下，必须进行多次移植。拟议项目的目标是 为了确定硫酸乙酰肝素蛋白聚糖，Syndecan-2如何调节HSC的维持和再生。 AIM 1将利用新生成的组织特异性基因敲除小鼠分析Syndecan-2在 调节HSC植入，同时对Syndecan-分子基序进行结构 - 功能分析 2在介导植入和利基再生中。 AIM 2将分析Syndecan-2在调节中的作用 通过在HSC的体内模型中结合辐射损伤和骨髓抑制，从应力中恢复造血 自我更新。这些实验将证明syndecan-2在中介HSC维护和 再生，提供基础知识，以进一步研究蛋白聚糖如何调节HSC。 从提议的目标完成后获得的知识期望具有广泛的潜力 作为接受化疗和放疗治疗的患者的贡献，作为其治疗方案的一部分 公共卫生的各种癌症，免疫疾病，白血病和贫血和治疗价值 治疗经历意外辐射暴露的患者的立场。 我的职业目标是成为顶级学术研究机构的助理教授。我瞄准 领导研究计划，该计划研究蛋白聚糖如何调节HSC和HSC微环境 在体内和压力期间。为了实现这些目标，拟议的项目已嵌入 对HSC从损伤中恢复进行建模，同时扩大我对糖生物学和生长因子信号传导的了解。 根据该奖项，我将在约翰·乔特（John Chute）博士（UCLA）的指导下进行拟议的培训 在HSC和利基再生的转化建模方面的丰富经验，同时得到咨询的支持 具有干细胞生物学，生长因子信号传导和蛋白聚糖生物学专业知识的委员会。作为 博士后研究员，我将在国际会议和指导委员会中介绍我的作品 由该领域的专家组成。作为初级教师，我将接受实验室管理/领导层的培训，格兰特 写作，谈判和指导，以帮助我领导一个成功的研究团队。拟议的项目将允许 我在发展HSC生物学方面的技能时过渡到独立的研究职位。加州大学洛杉矶分校有 精湛的研究设施，专业发展资源和行政支持，这将提供 作为指导的博士后研究员，支持我的研究和职业发展的必要基础设施 最终，我向独立过渡。