The role of GSK3/PPAR-/mitophagy pathway in regulating hematopoia

GSK3/PPAR-/线粒体自噬通路在调节造血中的作用

• 批准号: 10365005
• 负责人: Jian Huang
• 金额: $ 52.44万
• 依托单位: CORIELL INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10365005
• 关键词: Acute Myelocytic Leukemia; Agonist; Alleles; Attenuated; Autophagocytosis; Biochemical; Biological Assay; Blood Cells; Bone Marrow; Bone Marrow Stem Cell Transplantation; Bone Marrow Transplantation; Cell Lineage; Clinical; Data; Daughter; Defect; Disease; Dysmyelopoietic Syndromes; Exhibits; Genes; Genetic; Glycogen Synthase Kinase 3; Goals; Hematological Disease; Hematology; Hematopoietic; Hematopoietic Stem Cell Research; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homeostasis; Impairment; Knock-out; Knowledge; Lipids; Mitochondria; Molecular; Mus; Organelles; PPAR delta; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Pharmacology; Phenotype; Phosphorylation; Play; Population; Property; Protein Isoforms; Publishing; RNA Interference; Regulation; Reporter; Role; System; Testing; Therapeutic; Transgenic Mice; Transplantation; Work; delta opioid receptor; exhaustion; fatty acid oxidation; genetic approach; hematopoietic differentiation; improved; in vivo; inhibitor; insight; knock-down; leukemia; lipid metabolism; loss of function; novel; preference; reconstitution; self-renewal; stem cell division; stem cell function; stem cell homeostasis; stem cells; stemness

The role of GSK3/PPAR-δ/FAO/mitophagy pathway in regulating hematopoietic stem cell homeostasis and function Abstract Hematopoietic stem cells (HSCs) possess the abilities to both produce stem cells, a property known as self-renewal, and give rise to all differentiated hematopoietic lineages. Clinically, HSCs are therapeutically valuable for transplantation in treatment of various hematologic malignances. Despite remarkable progress made in the research of HSCs during the past three decades, the molecular mechanisms regulating HSC homeostasis and function are still not fully understood. Our previous published showed that GSK3 plays an essential role in regulating HSC homeostasis. Specifically, knockdown of Gsk3 promote transient expansion and long-term exhaustion of HSC in vivo. Our new preliminary studies demonstrated that GSK3 functions through PPAR-δ/FAO/mitophagy pathway to regulate HSC division symmetry; inhibition of GSK3 induces mitophagy and conversely, blocking PPAR-δ/FAO/mitophagy can reverse the enhanced self-renewal phenotype that is associated with GSK3 inhibition. In this study, we will first examine how GSK3 regulates PPAR-δ, which in turn regulates mitophagy and HSC division symmetry. Secondly, we will investigate whether loss-of- function of Ppar-δ, Park2 or Pink1 (two mitophagy key regulators) reverse the functional defect of Gsk3b-deficient HSC in vivo. Lastly, we will explore whether GSK3 controls FAO and lipid metabolism to regulate HSC function and homeostasis. Our study will provide significant new insights into the molecular mechanisms underlying GSK3-dependent regulation of HSC homeostasis and function. The knowledge learned may facilitate bone marrow transplantation for treating diverse hematological diseases.

GSK3/PPAR-δ/FAO/线粒体自噬通路的调节作用 造血干细胞稳态和功能 抽象的 造血干细胞 (HSC) 具有产生干细胞的能力， 被称为自我更新的特性，并产生所有分化的造血谱系。 临床上，HSCs对于移植治疗各种疾病具有治疗价值。 尽管造血干细胞的研究取得了显着进展。 在过去的三十年里，调节HSC稳态的分子机制 和功能还没有被完全理解。 我们之前发表的文章表明 GSK3 在调节 HSC 中发挥着重要作用 具体来说，Gsk3 的敲低可促进短暂的扩张和长期的扩张。 我们新的初步研究表明 GSK3 具有体内 HSC 的功能。 通过PPAR-δ/FAO/线粒体自噬途径调节HSC分裂对称性抑制； GSK3 诱导线粒体自噬，相反，阻断 PPAR-δ/FAO/线粒体自噬可以 逆转与 GSK3 抑制相关的增强的自我更新表型。 在这项研究中，我们将首先研究 GSK3 如何调节 PPAR-δ，进而调节 PPAR-δ 其次，我们将研究线粒体自噬和 HSC 分裂对称性是否丢失。 Ppar-δ、Park2 或 Pink1（两个线粒体自噬关键调节因子）的功能逆转了功能 体内Gsk3b缺陷型HSC的缺陷最后，我们将探讨GSK3是否控制FAO。 和脂质代谢来调节 HSC 功能和体内平衡。 我们的研究将为潜在的分子机制提供重要的新见解 HSC 稳态和功能的 GSK3 依赖性调节 学到的知识。 可以促进骨髓移植以治疗多种血液疾病。