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: 10545088
• 负责人: Jian Huang
• 金额: $ 51.19万
• 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/10545088
• 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; Learning; Lipids; Mitochondria; Molecular; Mus; Organelles; PPAR delta; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phenotype; Phosphorylation; Play; Population; Preleukemia; Property; Protein Isoforms; Publishing; RNA Interference; Regulation; Reporter; Role; System; Testing; Therapeutic; Transgenic Mice; Transplantation; Work; exhaustion; fatty acid oxidation; genetic approach; hematopoietic differentiation; hematopoietic stem cell expansion; improved; in vivo; inhibitor; insight; knock-down; leukemia; lipid metabolism; loss of function; novel; pharmacologic; 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.

GSK 3/PPAR-δ/FAO/线粒体自噬途径在调节细胞凋亡中的作用 造血干细胞稳态和功能 摘要 造血干细胞（HSC）具有产生干细胞， 这种特性称为自我更新，并产生所有分化的造血谱系。 在临床上，HSC对于移植治疗各种疾病是有治疗价值的。 血液恶性肿瘤尽管造血干细胞的研究取得了显著进展， 在过去的三十年中，调控HSC稳态的分子机制 和功能仍然没有完全理解。 我们以前的研究表明，GSK 3在调节HSC中起着重要作用， 体内平衡具体地，Gsk 3的敲低促进瞬时扩增和长期扩增。 体内HSC耗竭。我们新的初步研究表明，GSK 3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 GSK 3诱导线粒体自噬，相反，阻断PPAR-δ/FAO/线粒体自噬可 逆转与GSK 3抑制相关的增强的自我更新表型。在 在这项研究中，我们将首先研究GSK 3如何调节PPAR-δ，从而调节 线粒体自噬和HSC分裂对称性。其次，我们将调查是否失去- Ppar-δ、Park 2或Pink 1（两种线粒体自噬关键调节因子）的功能逆转了 Gsk 3b缺陷型HSC的体内缺陷。最后，我们将探讨GSK 3是否控制粮农组织。 和脂质代谢来调节HSC功能和稳态。 我们的研究将提供重要的新见解的分子机制， HSC稳态和功能的GSK 3依赖性调节。所学知识 可促进骨髓移植用于治疗多种血液病。