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

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)是治疗包括骨髓移植在内的造血功能紊乱的一种救命方法。 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 Hct的细胞(HSC)；然而，Cb Hct受到单个Cb单位中HSC数量较低的限制。因此， 迫切需要提高每个CB中的功能能力和/或功能HSC的数量 提高红细胞压积的治疗必须加以改进或补充新的治疗方法。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员地位- 他的研究将集中于确定改善HSC功能的方法，以提高HSC的功能 寻找新的治疗方法以提高对免疫缺陷患者造血功能障碍的治疗效果。 证明了患者的治疗结果。调查员目前的职业目标是顺利完成他的职位- 博士培训和过渡到独立研究人员的职位。他将通过寻找GUID来实现这一点- 从专家导师那里获得帮助，提高自己的技术和科学技能，并培养对职业生涯至关重要的技能 独立调查员职位。作为一名独立调查员，他将寻求提供对礼仪的洞察 为了利用细胞生物学、生物化学和小鼠模型支持的组学方法改善HSC的功能- 高血压病患者的Ling正在接近。相关研究计划的目标是阐明可以 有针对性地加强CB HSC功能，并生成足够的初步数据以提交有竞争力的 在获奖的最后一年申请R01。具体地说，研究计划建议检查组合 已知可增强HSC功能的治疗方法，如二肽基肽酶4(DPP4)抑制和 对HSC进行物理分离，以确定这些组合是相加的、协同的，还是没有进一步的影响。 完美无瑕。这项拟议的研究将检查已知的治疗方法引起的转录和表观基因组变化 改善小鼠近期归巢和早期移植的HSC功能和转录组 Hct将与移植到受体小鼠的细胞池进行比较分析。这些数据将产生洞察力 转化为共同和独特的基因程序，这些基因程序对造血干细胞的功能和植入非常重要。这项研究将 提供可以通过抑制或稳定来靶向的候选基因，以改善HSC的功能并植入- 并将使用用于HCT的小鼠模型来检查它们的重要性。综上所述，这种方法将认识到- 确定新的潜在治疗方式，以提高红细胞压积。申请人雄厚的职业发展计划，GUID- 来自他杰出的指导团队，环境在国际公认的顶级研究 印第安纳大学医学院研究所，并完成了研究AP中的拟议目标- Proach将为他管理一个专注于以下领域的学术实验室做好准备 可以用来改善无序造血患者预后的分子机制。