Metabolic regulation of hematopoietic stem cells

 描述（由申请人提供）：线粒体代谢失调与多种造血系统疾病相关，包括血液恶性肿瘤。然而，线粒体代谢如何协调造血细胞的发育仍不清楚。缺乏这种知识阻碍了对这些疾病的理解和治疗方法的发展。在之前的资助期间，我们证明了PTPMT 1，一种Pten样线粒体磷脂酰肌醇磷酸磷酸酶，在造血干细胞（HSC）中起着独特而关键的作用。PTPMT 1的缺失导致造血功能衰竭，这是由于细胞周期的变化和HSC分化的完全阻断。引人注目的是，在基因敲除小鼠中，HSC的绝对数量增加了约25倍。此外，尽管PTPMT 1从整个造血系统（包括HSC）中的耗竭导致造血功能衰竭和出生后致死，但骨髓、T淋巴或B淋巴谱系特异性敲除小鼠未显示任何表型，强烈表明PTPMT 1对干细胞特别重要，但对分化谱系祖细胞不重要。线粒体 PTPMT 1缺失的干/祖细胞（LSK）和谱系祖细胞的有氧代谢降低，而胞质糖酵解增强。然而，PTPMT 1缺陷改变细胞代谢和严重失调干细胞活性的详细细胞和分子机制仍有待确定。本次更新申请的目的是通过明确PTPMT 1的作用和作用机制，进一步了解HSC的代谢调控。核心假设是PTPMT 1通过控制线粒体代谢和胞质糖酵解之间的平衡来协调HSC活动（自我更新、分化和转化）。这一假设是根据我们在上一个供资周期的工作和最近的初步研究提出的。我们计划通过追求以下三个目标来检验我们的假设并实现本提案的目标。1）。目的：明确PTPMT 1在造血过程中发挥关键作用的细胞机制。2）。确定PTPMT 1缺陷重新编程细胞代谢的分子机制。3）。探讨PTPMT 1在白血病干细胞和祖细胞转化中的作用。本申请中提出的研究将极大地促进我们对协调线粒体代谢/生物能量学、糖酵解和β-氨基分解如何协调HSC生物学的理解。这些数据将有助于更深入地了解与线粒体功能失调相关的血液疾病的病理生理学，这将有助于确定这些疾病的新型治疗干预的分子靶点。

 DESCRIPTION (provided by applicant): Deregulated mitochondrial metabolism is associated with a variety of hematopoietic disorders, including hematological malignancies. However, it remains poorly defined how mitochondrial metabolism coordinates hematopoietic cell development. Lack of such knowledge impedes understanding of and development of therapeutics for these diseases. In the previous funding period we demonstrated that PTPMT1, a Pten-like mitochondrial phosphatidylinositol phosphate phosphatase, plays a unique and crucial role in hematopoietic stem cells (HSCs). Deletion of PTPMT1 resulted in hematopoietic failure due to changes in the cell cycle and a complete block in the differentiation of HSCs. Strikingly, the absolute number of HSCs was increased by ~25-fold in the knockout mice. Moreover, although depletion of PTPMT1 from the entire hematopoietic system (including HSCs) caused hematopoietic failure and postnatal lethality, myeloid, T lymphoid, or B lymphoid lineage-specific knockout mice did not show any phenotypes, strongly suggesting that PTPMT1 is specifically important for stem cells, but not differentiated lineage progenitors. Mitochondrial aerobic metabolism of PTPMT1-depleted stem/progenitor (LSK) cells and lineage progenitors was decreased while cytosolic glycolysis was enhanced. Nevertheless, the detailed cellular and molecular mechanisms by which PTPMT1 deficiency alters cellular metabolism and profoundly deregulates stem cell activities remain to be determined. The objective of this renewal application is to further understand the metabolic regulation of HSCs by defining the role and acting mechanisms of PTPMT1. The central hypothesis is that PTPMT1 coordinates HSC activities (self-renewal, differentiation, and transformation) by controlling the balance between mitochondrial metabolism and cytosolic glycolysis. This hypothesis has been formulated on the basis of our work in the last funding cycle and recent preliminary studies. We plan to test our hypothesis and accomplish the objectives of this proposal by pursuing the following three aims. 1). To define the cellular mechanisms of the crucial role of PTPMT1 in hematopoiesis. 2). To determine the molecular mechanisms by which PTPMT1 deficiency reprograms cellular metabolism. 3). To investigate the role of PTPMT1 in leukemic transformation of stem cells and progenitors. The studies proposed in this application will greatly advance our understanding of how coordinated mitochondrial metabolism/bioenergetics, glycolysis, and glutaminolysis orchestrate HSC biology. These data will contribute to a much deeper understanding of the pathophysiology of blood disorders associated with deregulated mitochondrial function, which will help identify molecular targets for novel therapeutic interventions for these diseases.