Flow, Fatty Acid Biosynthesis, and Hematopoiesis

流动、脂肪酸生物合成和造血

基本信息

批准号：
10868960
负责人：
Longhou Fang
金额：
$ 15万
依托单位：
METHODIST HOSPITAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10868960
关键词：
Acceleration Anemia Aorta Attenuated Binding Binding Proteins Blood Blood Vessels Blood flow Cell Fate Control Cell Nucleus Cells Data Development Dinoprostone Disease Docosahexaenoic Acids Eicosanoids Embryonic Development Endothelial Cells Endothelium Engineering Engraftment Exposure to Fatty Acids Friction Future Generations Genes Genetic Transcription Gonadal structure Hematologic Neoplasms Hematological Disease Hematology Hematopoiesis Hematopoietic Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human Immune Immune System Diseases Impairment In Vitro Knowledge Liquid substance Literature Mesonephric structure Metabolic Diseases Mission Molecular Molecular Chaperones Morbidity - disease rate Mus Mutation Nuclear Omega-3 Fatty Acids Outcome Output Pathway interactions Patients Phase Physical condensation Pilot Projects Polyunsaturated Fatty Acids Population Procedures Proliferating Protein Inhibition Public Health Publications Regulatory Element Regulatory Pathway Research SCAP protein Scientist Signal Transduction Specific qualifier value Sterols Supplementation System TP53 gene Testing Therapeutic Transcription Coactivator Transcriptional Regulation Umbilical Cord Blood United States National Institutes of Health Work Zebrafish cell fate specification cellular engineering chemotherapy cofactor disability donor stem cell fatty acid biosynthesis heart function hematopoietic cell transplantation hematopoietic stem cell emergence hematopoietic stem cell fate hemogenic endothelium immune function improved in vivo induced pluripotent stem cell irradiation lipid biosynthesis lipid metabolism mechanical properties mortality novel overexpression programs protein expression reconstitution response shear stress stem cells transcription factor

项目摘要

(PLEASE KEEP IN WORD, DO NOT PDF) Hematopoietic stem cells (HSCs), which give rise to the full spectrum of hematological cells in the blood, hold tremendous promise as future treatments for hematological and immunological diseases. For example, HSC transplantation can reconstitute the blood system following irradiation or chemotherapy, thus restoring immune function and improving anemia in patients undergoing such treatments. Furthermore, therapies that could modulate the regulatory pathways controlling cell fate could help treat metabolic disorders caused by unrestricted proliferation of HSCs and hematopoietic progenitor cells. Unfortunately, to date scientists have limited capability to expand multipotent HSCs ex vivo from cord blood. Even with sufficient HSCs, if they are not properly engrafted, transplanted HSCs can cause serious morbidity or mortality. Finally, compatibility challenges between HSC donors and recipients create additional difficulty. These challenges impede the broader application of hematopoietic cell transplantation procedures. One attractive alternative is to generate HSCs in vitro using cell engineering. The overall objective of this application is to identify the key molecular mechanisms controlling HSC emergence during embryonic development. This knowledge can be harnessed to guide de novo generation of HSPCs in vitro. Preliminary results have led to the rationale that fatty acid biosynthesis–activated by shear stress imposed on the vascular wall–dictates hematopoietic development. These pilot studies have revealed a novel flow-regulated lipid metabolism program orchestrating hematopoiesis. Based on rigorous preliminary research and previous publications by this team and others, the central hypothesis is that endogenous fatty acid biosynthesis facilitates HSPC fate commitment from human-induced pluripotent stem cells. The central hypothesis will be investigated through two specific aims that will examine whether the natural fatty acid synthesis program controls HSPC fate specification from human-induced pluripotent stem cells. Upon completion of this work, the results will define a critical flow-regulated lipid metabolism pathway that instructs definitive hematopoiesis.

（请以 WORD 形式保存，请勿以 PDF 形式保存）造血干细胞（HSC）在血液中产生全谱的血液细胞，作为未来血液和免疫疾病的治疗方法具有巨大的前景，例如，HSC 移植可以在放射或化疗后重建血液系统，从而恢复免疫。此外，能够调节控制细胞命运的调节途径的疗法可以帮助治疗由 HSC 和造血不受限制增殖引起的代谢紊乱。不幸的是，迄今为止，科学家从脐带血中离体扩增多能 HSC 的能力有限，即使有足够的 HSC，如果移植不当，移植的 HSC 也会导致严重的发病或死亡。这些挑战阻碍了造血细胞移植手术的更广泛应用。一种有吸引力的替代方案是利用细胞工程在体外生成 HSC，该应用的总体目标是确定胚胎发育过程中控制 HSC 出现的关键分子机制，可利用这一知识来指导体外生成 HSPC。得出的基本原理是，由施加在血管壁上的剪切应力激活的脂肪酸生物合成决定造血发育，这些试点研究揭示了一种新的流量调节脂质代谢程序的协调。基于该团队和其他人的严格初步研究和之前的出版物，中心假设是内源性脂肪酸生物合成促进人类诱导多能干细胞的 HSPC 命运决定。该中心假设将通过两个具体目标进行研究。天然脂肪酸合成程序是否控制人诱导多能干细胞的 HSPC 命运规范。完成这项工作后，结果将定义一个关键的流量调节脂质代谢途径，指导明确的。造血作用。