Fatty acid/branched-chain amino acid metabolism in hematopoietic stem cells

造血干细胞中的脂肪酸/支链氨基酸代谢

• 批准号: 8896218
• 负责人: Charles Leslie Hoppel
• 金额: $ 10.3万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-10 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8896218
• 关键词: Acute Promyelocytic Leukemia; Adult; Affect; Amino Acids; Apoptosis; Area; Biological; Biology; Blood Cells; Bone Marrow; Branched-Chain Amino Acids; Carnitine; Catabolism; Cell Count; Cell Respiration; Cell division; Cell physiology; Cells; Collaborations; D-Aspartic Acid; DNA Damage; Defect; Development; EP300 gene; Embryo; Exhibits; Exposure to; Family; Fatty Acids; Future; Gene Pool; Genes; Gluconeogenesis; Glutamic Acid; Glycolysis; Goals; Hematological Disease; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Homeostasis; Hypoxia; Knock-out; Knockout Mice; Link; Lipids; Maintenance; Metabolic; Metabolism; Methods; Microarray Analysis; Mission; Mitochondria; Mitochondrial Diseases; Modeling; Molecular; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Oxidative Phosphorylation; PPAR gamma; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Phenotype; Play; Reactive Oxygen Species; Regenerative Medicine; Regulation; Research; Role; Signal Transduction; Tail; Techniques; Technology; Testing; Therapeutic; Trans-Activators; Yang; adult stem cell; fatty acid metabolism; fatty acid oxidation; lipid metabolism; meetings; metabolomics; new therapeutic target; novel; programs; public health relevance; receptor; reconstitution; research study; self-renewal; stem cell biology; stem cell population

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to identify and characterize molecules and pathways that impact the metabolism and function of hematopoietic stem cells (HSCs). Specifically, the application will test the hypothesis that branched-chain amino acid/fatty acid (BCAA/FA) oxidation plays a critical role in controlling HSC functions. HSCs are defined by their ability to self-renew and to give rise to multi-lineages of blood cells. n adults, the HSC population resides in the hypoxic bone marrow microenvironment and remains relatively quiescent. How HSCs remain quiescent, but can rapidly reprogram themselves to be metabolically ready for subsequent differentiation and mobilization to maintain homeostasis is totally unknown. Although several studies have begun to investigate the relationship between metabolism and HSC function, most of the studies focused on glycolysis and energy homeostasis but not the contribution of lipid and amino acid catabolism on HSC functions. We have previously shown that conditional knockout (KO) of Cited2 [CBP/p300-interacting transactivators with glutamic acid (E) and aspartic acid (D)-rich tail 2] in the mouse results in increased HSC apoptosis, loss of quiescence and increased cycling, thus leading to severely impaired hematopoietic reconstitution capacity. Our recent global metabolomics analysis using LT-HSCs isolated from WT and Cited2 KO mice identified branched-chain amino acid/fatty acid (BCAA/FA) metabolism as one of the major metabolic differences between WT and Cited2 KO HSCs. Recently, a previously unknown promyelocytic leukemia (PML)-perioxisome proliferator-activated receptor δ (PPARδ)-fatty acid oxidation (FAO) pathway was shown to be crucial for the maintenance of HSCs and the control of asymmetric cell division. Interestingly, others have shown that Cited2 interacts with PPAR family of nuclear receptors that control lipid metabolism. In addition, Cited2 plays a role in gluconeogenesis through its regulation of PGC-1α (PPAR gamma coactivator-1α)actions and could be a novel therapeutic target for type II diabetes. Because of the molecular and biological link of Cited2 to PPAR and overlapping phenotypes of Cited2 and PML knockout mice (FAO), this multi-PI application intends to test the hypothesis that Cited2 acts as a functional node to modulate branched-chain amino acid and fatty acid metabolism in controlling HSC functions by two subaims: 1: To identify intermediates within the branched-chain amino acid and fatty acid metabolism that impact the function of HSCs from Cited2 knockout mice. 2: To determine mechanistically how Cited2 modulates the BCAA/FA oxidation in HSCs. The current application represents a focused synergistic new collaboration between Drs. Yang and Hoppel to investigate the role of Cited2 in BCAA/FA oxidation in HSCs, an under-explored research area in hematopoiesis. The findings may provide new means of controlling HSC cell fate with future therapeutic implications. The study therefore is "tightly focused and directed at validating novel concepts and approaches that promise to open up new pathways for discovery" and fits the mission of the SHINE-II program at NIDDK.

描述（由申请人提供）：该提案的长期目标是识别和表征影响造血干细胞（HSC）代谢和功能的分子和途径。具体来说，该应用程序将测试支链氨基酸/脂肪酸 (BCAA/FA) 氧化在控制 HSC 功能中发挥关键作用的假设。 HSC 的定义是其自我更新和产生多谱系血细胞的能力。在成人中，HSC 群存在于缺氧的骨髓微环境中并保持相对静止。 HSC 如何保持静止状态，但能够快速重新编程，为随后的分化和动员以维持体内平衡做好代谢准备，目前尚不清楚。尽管已有一些研究开始探讨代谢与 HSC 功能之间的关系，但大多数研究集中在糖酵解和能量稳态，而不是脂质和氨基酸分解代谢对 HSC 功能的贡献。我们之前已经证明，小鼠中 Cited2 [CBP/p300 相互作用的反式激活子与富含谷氨酸 (E) 和天冬氨酸 (D) 的尾部 2] 的条件敲除 (KO) 会导致 HSC 凋亡增加、静止性丧失和循环增加，从而导致造血重建能力严重受损。我们最近使用从 WT 和 Cited2 KO 小鼠分离的 LT-HSC 进行的全球代谢组学分析发现，支链氨基酸/脂肪酸 (BCAA/FA) 代谢是 WT 和 Cited2 KO HSC 之间的主要代谢差异之一。最近，一种以前未知的早幼粒细胞白血病（PML）-过氧化物酶体增殖物激活受体δ（PPARδ）-脂肪酸氧化（FAO）途径被证明对于HSC的维持和不对称细胞分裂的控制至关重要。有趣的是，其他人已经表明 Cited2 与控制脂质代谢的 PPAR 核受体家族相互作用。此外，Cited2 通过调节 PGC-1α (PPAR gamma coactivator-1α) 的作用在糖异生中发挥作用，可能成为 II 型糖尿病的新治疗靶点。由于 Cited2 与 PPAR 的分子和生物学联系以及 Cited2 和 PML 敲除小鼠 (FAO) 的重叠表型，该多 PI 应用旨在测试以下假设：Cited2 作为功能节点调节支链氨基酸和脂肪酸代谢，通过两个子目标控制 HSC 功能： 1：鉴定支链氨基酸内的中间体 酸和脂肪酸代谢影响 Cited2 敲除小鼠 HSC 的功能。图 2：从机制上确定 Cited2 如何调节 HSC 中的 BCAA/FA 氧化。当前的应用代表了博士之间的重点协同新合作。 Yang 和 Hoppel 旨在研究 Cited2 在 HSC 中 BCAA/FA 氧化中的作用，这是一个尚未探索的造血研究领域。这些发现可能提供控制 HSC 细胞命运的新方法，并具有未来的治疗意义。因此，这项研究“紧密关注并旨在验证有望开辟新发现途径的新概念和方法”，并且符合 NIDDK SHINE-II 项目的使命。