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

GSK3/PPAR-δ/FAO/丝裂原吞噬通路在调控中的作用 造血干细胞的动态平衡和功能 摘要 造血干细胞(HSCs)既有产生干细胞的能力，也有 被称为自我更新的属性，并产生所有分化的造血血统。 在临床上，造血干细胞对于移植治疗各种疾病具有重要的治疗价值。 恶性血液病。尽管在造血干细胞研究方面取得了显著进展 在过去的三十年里，调节HSC动态平衡的分子机制 和功能仍未完全了解。 我们之前发表的研究表明，GSK3在调节HSC中起着重要作用 动态平衡。具体地说，GSK3的敲除促进了短暂的扩张和长期的 体内肝星状细胞的耗竭。我们新的初步研究表明GSK3功能 通过PPAR-δ/FAO/有丝分裂噬菌体途径调节肝星状细胞分裂对称性；抑制 阻断PPAR-δ/粮农组织/有丝分裂原吞噬 逆转与GSK3抑制相关的增强的自我更新表型。在……里面 在这项研究中，我们将首先研究GSK3是如何调节PPAR-δ的，而PPAR-RNA3又调节 有丝分裂和HSC分裂对称性。其次，我们将调查损失是否- PPAR-δ、PARK2或PINK1(两个有丝分裂关键调节因子)的功能逆转功能 体内Gsk3b缺陷型HSC的缺陷。最后，我们将探讨GSK3是否控制粮农组织 和脂代谢，调节HSC功能和动态平衡。 我们的研究将对潜在的分子机制提供重要的新见解。 GSK3依赖的HSC动态平衡和功能调节。学到的知识 可促进骨髓移植治疗各种血液病。

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.