Omics interrogation of functionally competent hematopoieitic stem cells

项目总结/摘要 造血细胞移植（HCT）是一种挽救生命的治疗造血功能紊乱，包括恶性肿瘤， 恶性和非恶性疾病。脐带血是一种很有前途的造血干细胞来源 然而，CB HCT受到单个CB单位中存在的低HSC数量的限制。因此，在本发明中， 迫切需要提高每个CB中功能性HSC的功能能力和/或数量 单位，和治疗，以提高HCT必须改善或补充新的治疗。申请人的 长期的目标是建立自己作为一个独立的调查员在一个杰出的学术研究- 他的研究将集中在确定如何改善HSC功能以增强HCT， 本发明的目的是发现新的治疗方式以改善对骨髓增生异常综合征的造血障碍的治疗， 患者的结果。调查员的直接职业目标是成功完成其职务， 博士培训和过渡到一个独立的调查员的位置。他将通过寻求指导来实现这一目标。 从专家导师的机会，提高他的技术科学技能和发展职业技能，重要的是一个 独立调查员职位。作为一名独立的调查员，他将寻求提供洞察力的礼仪， 利用细胞生物学、生物化学和小鼠模型支持的组学方法改善HSC功能- HCT的方法。相关研究计划的目标是阐明分子程序， 旨在增强CB HSC功能，并生成足够的初步数据，以提交竞争性 R 01申请在获奖的最后一年。具体而言，研究计划建议检查组合 已知增强HSC对HCT的功能的治疗，如二肽基肽酶4（DPP 4）抑制和 HSC的物理毒性分离，以确定这些组合是否是相加的、协同的或没有进一步的作用。 完美。这项拟议的研究将检查已知的治疗引起的转录组和表观基因组变化， 改善HSC功能以及最近归巢和早期移植的HSC的转录组， 将对HCT与移植至受体小鼠的细胞池进行比较分析。这些数据将产生洞察力 共同和独特的基因程序，这是重要的HSC功能和移植。本研究将 提供可通过抑制或稳定作用靶向的候选基因，以改善HSC功能和植入- 并将使用HCT的小鼠模型来检查它们的重要性。综合考虑，这种方法将确定- 确定新的潜在治疗方式，以提高HCT。申请人强大的职业发展计划，指南- 从他杰出的指导团队，环境在国际公认的顶级研究 机构的印第安纳州大学医学院，并完成了拟议的目标，在研究ap- proach将为他准备一个富有成效和高度影响力的职业生涯，管理一个学术实验室，重点是 分子机制，可以利用，以改善患者的结果为造血功能障碍。

Project Summary/ Abstract Hematopoietic cell transplantation (HCT) is a life-saving treatment for disordered hematopoiesis, including ma- lignant and non-malignant diseases. Umbilical cord blood (CB) is a promising source of hematopoietic stem cells (HSCs) for HCT; however, CB HCT is limited by the low HSC numbers present in single CB units. Thus, there is a critical need to improve the functional competency and/or number of functional HSCs in each CB unit, and treatments to enhance HCT must be improved or supplemented with new treatments. The applicant's long-term goal is to establish himself as an independent investigator at an outstanding academic research in- stitution where his studies will focus on identifying ways to improve HSC function for enhanced HCT, with the goal of discovering novel therapeutic modalities to improve treatment for disordered hematopoiesis for im- proved patient outcomes. The investigator’s immediate career objectives are to successfully complete his post- doctoral training and transition to an independent investigator position. He will accomplish this by seeking guid- ance from expert mentors, improving his technical scientific skillset and developing career skills important to an independent investigator position. As an independent investigator, he will seek to provide insight into manners to improve HSC function using omics approaches supported with cell biology, biochemistry and mouse model- ling of HCT approaches. The goal of the associated research plan is to elucidate molecular programs that can be targeted to enhance CB HSC function and to generate sufficient preliminary data to submit a competitive R01 application in the final year of the award. Specifically, the research plan proposes examining combinations of treatments known to enhance HSC function for HCT, such as Dipeptidyl peptidase 4 (DPP4) inhibition and physioxic isolation of HSCs, to determine if these combinations are additive, synergistic, or have no further ef- fect. The proposed study will examine transcriptomic and epigenomic changes induced by treatments known to improve HSC function and the transcriptome of recently homed and early engrafted HSCs in a mouse model of HCT will be analyzed compared with the pool of cells transplanted to recipient mice. This data will yield insights into common and unique gene programs that are important for HSC function and engraftment. This study will provide candidate genes that can be targeted by inhibition or stabilization to improve HSC function and engraft- ment and will examine their importance using mouse models for HCT. Taken together, this approach will iden- tify new potential treatment modalities to enhance HCT. The applicant’s strong career development plan, guid- ance from his outstanding mentoring team, the environment at the internationally recognized top tier research institution of Indiana University School of Medicine, and completion of the proposed aims in the research ap- proach will prepare him for a productive and highly impactful career managing an academic lab focused on molecular mechanisms that can be exploited to improve patient outcomes for disordered hematopoiesis.