Omics interrogation of functionally competent hematopoieitic stem cells

功能健全的造血干细胞的组学研究

• 批准号: 10571101
• 负责人: James Patrick Ropa
• 金额: $ 10.6万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-15 至 2024-07-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10571101
• 关键词: Affect; Air; Award; Biochemistry; Blood Cells; Blood Platelets; Bone Marrow; Candidate Disease Gene; Cell Count; Cell Transplantation; Cells; Cellular biology; Clinical; Collection; Combined Modality Therapy; Competence; Cryopreservation; Data; Development Plans; Dipeptidyl Peptidases; Disease; Engraftment; Environment; Exposure to; Future; Genes; Goals; HLA Antigens; Harvest; Hematological Disease; Hematologist; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; High Dose Chemotherapy; Human; Immunophenotyping; Indiana; Institution; International; Life; Longevity; Malignant - descriptor; Mentors; Methods; Modality; Molecular; Molecular Profiling; Mus; Non-Malignant; Non-Neoplastic Hematologic and Lymphocytic Disorder; Nuclear Protein; Outcome; Oxygen; Pathway interactions; Patient-Focused Outcomes; Patients; Positioning Attribute; Productivity; Professional Competence; Public Health; Radiation; Recovery; Research; Research Personnel; Risk; Shock; Source; Stress; Testing; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Universities; career; career development; cell killing; epigenomic profiling; epigenomics; extracellular; graft vs host disease; hematopoietic cell transplantation; hematopoietic engraftment; improved; insight; loss of function; medical schools; mouse model; neutrophil; novel; novel therapeutics; peripheral blood; post-doctoral training; programs; reconstitution; side effect; single-cell RNA sequencing; skills; stem cell function; stem cells; transcriptome; transcriptomics; transplant model; Affect; Air; Award; Biochemistry; Blood Cells; Blood Platelets; Bone Marrow; Candidate Disease Gene; Cell Count; Cell Transplantation; Cells; Cellular biology; Clinical; Collection; Combined Modality Therapy; Competence; Cryopreservation; Data; Development Plans; Dipeptidyl Peptidases; Disease; Engraftment; Environment; Exposure to; Future; Genes; Goals; HLA Antigens; Harvest; Hematological Disease; Hematologist; Hematopoiesis; Hematopoietic; Hematopoietic System; Hematopoietic stem cells; High Dose Chemotherapy; Human; Immunophenotyping; Indiana; Institution; International; Life; Longevity; Malignant - descriptor; Mentors; Methods; Modality; Molecular; Molecular Profiling; Mus; Non-Malignant; Non-Neoplastic Hematologic and Lymphocytic Disorder; Nuclear Protein; Outcome; Oxygen; Pathway interactions; Patient-Focused Outcomes; Patients; Positioning Attribute; Productivity; Professional Competence; Public Health; Radiation; Recovery; Research; Research Personnel; Risk; Shock; Source; Stress; Testing; Transplantation; Umbilical Cord Blood; Umbilical Cord Blood Transplantation; Universities; career; career development; cell killing; epigenomic profiling; epigenomics; extracellular; graft vs host disease; hematopoietic cell transplantation; hematopoietic engraftment; improved; insight; loss of function; medical schools; mouse model; neutrophil; novel; novel therapeutics; peripheral blood; post-doctoral training; programs; reconstitution; side effect; single-cell RNA sequencing; skills; stem cell function; stem cells; transcriptome; transcriptomics; transplant model

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.

项目摘要/摘要 造血细胞移植（HCT）是一种挽救生命的造血疗法，包括MA- 症状和非恶性疾病。脐带血（CB）是造血茎的有前途的来源 HCT的细胞（HSC）；但是，CB HCT受单个CB单元中存在的低HSC数量的限制。那， 在每个CB中提高功能能力和/或功能HSC的数量迫切需要 必须改善或补充新的治疗方法，并通过新的治疗方法进行新的治疗方法。申请人的 长期目标是在一项杰出的学术研究中确立自己的独立研究者 条件他的研究将集中于确定改善HSC功能的方法以增强HCT的方法 发现新型的热模式的目标，以改善无序造血治疗的治疗方法 经过验证的患者结果。调查员的直接职业目标是成功完成他的职位 - 博士培训和过渡到独立研究者职位。他将通过寻求指南来实现这一目标 - 专家导师的ance，提高他的技术科学技能和发展职业技能对 独立研究者职位。作为独立调查员，他将寻求对举止的见解 使用由细胞生物学，生物化学和小鼠模型支持的OMICS方法提高HSC功能 HCT方法的链条。相关研究计划的目的是阐明可以 针对增强CB HSC功能并生成足够的初步数据以提交竞争性的数据 奖励的最后一年R01申请。具体而言，研究计划提案检查组合 已知可以增强HSC功能的HSC功能的处理，例如二肽基肽酶4（DPP4）抑制和 HSC的生理Xy隔离，以确定这些组合是加性的，协同的还是没有进一步的EF- 拟议的研究将检查已知已知的治疗诱导的转录组和表观基因组变化 改善HSC功能和最近归属和早期植入HSC的转录组 与移植到受体小鼠的细胞池相比，将对HCT进行分析。这些数据将产生见解 进入对HSC功能和植入很重要的常见和独特的基因程序。这项研究会 提供可以通过抑制或稳定来靶向的候选基因，以改善HSC功能并植入 使用鼠标模型对HCT进行研究，并将检查其重要性。综上所述，这种方法将与 提出新的潜在治疗方式以增强HCT。申请人的强大职业发展计划，指南 - 来自他杰出的心理团队，国际公认的顶级研究的环境 印第安纳大学医学院，并完成了拟议的目的 Proach将为他做好一个富有成效且高度影响力的职业，以管理着专注于的学术实验室 可以探索以改善无序造血的患者结局的分子机制。