Basic and Translational Research of iPSC-Based hematologic and Vascular Therapies

基于 iPSC 的血液和血管治疗的基础和转化研究

• 批准号: 7939701
• 负责人: ALAN D FRIEDMAN
• 金额: $ 120.54万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939701
• 关键词: Adult; Bioinformatics; Blood Vessels; Cells; Collaborations; Complex; DNA Modification Methylases; Data; Developmental Biology; Endothelium; Ensure; Epigenetic Process; Event; Generations; Genetic; Genetic Transcription; Hematopoietic; Human; Knowledge; Lead; Marrow; Mediating; Molecular; Natural regeneration; Pathway interactions; Play; Protein Isoforms; Protocols documentation; Research; Research Project Grants; Role; Safety; Signal Transduction; Staging; Translational Research; Vascular Diseases; Work; base; cancer cell; coping; human embryonic stem cell; insight; member; metaplastic cell transformation; notch protein; novel; nuclear reprogramming; preclinical study; progenitor; stem cell fate; tumorigenic

DESCRIPTION (provided by applicant): The Stanford-Johns Hopkins Research Hub intends to gain a deeper understanding of molecular pathways to enhance the efficiency of nuclear reprogramming, to ensure the function and safety of induced pluripotentlal cells (iPSCs), to provide robust protocols for differentiation and purification of hematopoietic and endothelial lineages, and to guide pioneering work in pre-clinical studies of safety and efficacy. The Hopkins group proposes three research projects. PROJECT 1 (S. Baylin) proposes to characterize epigenetic events mediated by DNMT occuring during reprogramming to the stem cell fate and to manipulate these events to enhance reprogramming and avoid transformation. PROJECT 2 (E. Zambidis) proposes to characterize the human hemangioblast, taking advantage of the novel finding that this bipotent progenitor is expresses ACE, to manipulate ACE signaling to favor emergence of adult HSC, to utilize novel marrow stromal signals to favor emergence of adult HSC, and to determine the role of novel miRNAs identified as hemangioblast or HSC-specific in directing HSC specification. This project will also combine knowledge gained throughout our Hub and the Consortium to optimally generate and pre-clinically evaluate human IPSO and adult HSC. PROJECT 3 (A. Friedman) will identify the mechanisms allowing HSC specification by Runxl, a master transcriptional regulator of adult HSC emergence from hemogenic endothelium. The role of Runxl isoforms, Runxl phopshorylation, Runxl interaction with HDACs or Ets factors, and Runxl cooperation with Notch, Wnt, or BMP signaling will be evaluated. Identification of relevant Runxl genetic targets using global RNA expression and ChiP-chip or ChlP-Seq approaches will be undertaken, and expression analyses will seek novel regulators, expressed in HSC but not the hemangioblast. CORE activities conducted in collaboration with our Stanford colleagues will include epigenetic comparison of IPSC to cancer cells and to hESC (S. Baylin) and bioinformatics analysis of epigenetic, RNA expression, and ChIP data (L. Cope). We anticipate that these efforts will lead to basic insights in developmental biology and to novel, translational applications for hematologic and vascular disorders.

描述（由申请人提供）： The Stanford-Johns Hopkins Research Hub intends to gain a deeper understanding of molecular pathways to enhance the efficiency of nuclear reprogramming, to ensure the function and safety of induced pluripotentlal cells (iPSCs), to provide robust protocols for differentiation and purification of hematopoietic and endothelial lineages, and to guide pioneering work in pre-clinical studies of safety and efficacy.霍普金斯集团提出了三个研究项目。项目1（S. Baylin）建议表征由重新编程到干细胞命运期间发生的DNMT介导的表观遗传事件，并操纵这些事件以增强重编程并避免转化。 PROJECT 2 (E. Zambidis) proposes to characterize the human hemangioblast, taking advantage of the novel finding that this bipotent progenitor is expresses ACE, to manipulate ACE signaling to favor emergence of adult HSC, to utilize novel marrow stromal signals to favor emergence of adult HSC, and to determine the role of novel miRNAs identified as hemangioblast or HSC-specific in directing HSC specification.该项目还将结合整个枢纽和财团中获得的知识，以最佳地生成和链式链式评估人类IPSO和成人HSC。项目3（A。Friedman）将确定允许HSC规范的机制Runxl，Runxl是来自血肿内皮的成人HSC出现的主要转录调节剂。 RUNXL同工型，Runxl PhopShoryLation，RunXl与HDAC或ETS因子的相互作用以及与Notch，Wnt或BMP信号的RunXl合作的作用。将采用全局RNA表达和CHIP-CHIP或CHLP-SEQ方法来识别相关的RUNXL遗传靶标，并且表达分析将寻求在HSC中表达的新型调节剂，但不在Hemangioblast中表达。与我们的斯坦福大学合作进行的核心活动将包括IPSC与癌细胞和hESC（S. Baylin）的表观遗传学比较以及表观遗传学，RNA表达和芯片数据的生物信息学分析（L. COPE）。我们预计，这些努力将导致有关发育生物学的基本见解，以及新颖的血液学和血管疾病的转化应用。