The role of mitochondria in embryonic stem cells.

线粒体在胚胎干细胞中的作用。

• 批准号: 8653967
• 负责人: Jalees Rehman
• 金额: $ 29.41万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8653967
• 关键词: Affect; Apoptosis; Biogenesis; Biology; Blood Vessels; Calculi; Cell Cycle; Cell Differentiation process; Cell Proliferation; Cell Survival; Cell Therapy; Cells; Characteristics; Clinical; Commit; Consumption; Data; Deoxyglucose; Development; Dichloroacetate; Differentiation Antigens; Evaluation; Exhibits; Flow Cytometry; Future; GLS2 gene; Gene Expression; Genes; Glucose; Glutaminase; Glutamine; Goals; In Vitro; Intervention; Lead; Link; Medicine; Membrane Potentials; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Mus; Natural regeneration; Oxidation-Reduction; PDH kinase; PET/CT scan; Pathway interactions; Patients; Play; Plug-in; Pluripotent Stem Cells; Process; Proliferating; Proliferation Marker; Publishing; Respiration; Respiratory Chain; Role; Rotenone; Small Interfering RNA; Stem cells; Teratoma; Testing; Therapeutic; Therapeutic Uses; Tissues; Translating; Transplantation; Undifferentiated; angiogenesis; base; cancer cell; cell type; embryonic stem cell; extracellular; glucose metabolism; human embryonic stem cell; improved; in vivo; in vivo Model; injured; insight; interest; kinase inhibitor; mitochondrial membrane; novel; oxidation; pluripotency; pyruvate dehydrogenase; regenerative; regenerative therapy; research study; self-renewal; senescence; stem; stem cell differentiation; stem cell fate; stem cell therapy; transcription factor; uptake

DESCRIPTION (provided by applicant): Stem cells are characterized by their multi-lineage differentiation potential (pluripotency) and their ability for self-renewal, which permits them to proliferate while avoiding lineage commitment and senescence. There has been much interest in identifying the pathways by which stem cells choose between the cell fates of lineage commitment versus self-renewal. A better understanding of this process would allow for the development of specific modulators that direct stem cell fate and improve their utility for regenerative therapies. Recent studies have demonstrated that mitochondrial function regulates gene expression and self-renewal in multiple cell types but little is known about the role of mitochondrial function in embryonic stem cells. We therefore studied the mitochondrial function and activity in human embryonic stem cells (hESCs). Our novel preliminary data suggest that when compared to differentiated cells, undifferentiated hESCs have high mitochondrial biogenesis, but exhibit low levels of mitochondrial glucose oxidation. Based on our data and recent published findings, we have formulated the central hypothesis of the proposal glucose oxidation regulates self-renewal and differentiation of human embryonic stem cells (hESCs). We propose to evaluate this by testing the following three hypotheses: In Aim 1, we will assess the effect of modulating glucose oxidation on the metabolic activity of hESCs. In Aim 2, we will evaluate the effect of modulating glucose oxidation on the self-renewal and differentiation of hESCs. In Aim 3, we will assess how enhancing mitochondrial glucose oxidation affects the therapeutic use of hESC by using in vivo models of teratoma formation and angiogenesis. This proposal investigates a new paradigm, since there is no clearly established link yet between mitochondrial glucose oxidation and human ESC fate. The results from our study of are likely to yield major insights into cellular metabolic and regenerative processes. Since multiple pharmacological modulators of metabolism are currently available and have been approved for use in patients, we believe that our findings on metabolic processes in stem biology could be readily translated into the clinical setting to improve regenerative stem cell therapies.

描述（由申请人提供）：干细胞的特征是它们的多条不断分化潜力（多能性）及其自我更新能力，这使它们允许它们在避免谱系承诺和衰老的同时增殖。识别干细胞在谱系承诺与自我更新的细胞命运之间进行选择的途径引起了很大的兴趣。更好地理解这一过程将允许开发特定的调节剂，这些调节剂指导干细胞命运并改善其再生疗法的效用。最近的研究表明，线粒体功能调节多种细胞类型的基因表达和自我更新，但对线粒体功能在胚胎干细胞中的作用知之甚少。因此，我们研究了人类胚胎干细胞（HESC）中的线粒体功能和活性。我们新的初步数据表明，与分化细胞相比，未分化的hESC具有高线粒体生物发生，但线粒体葡萄糖氧化水平较低。根据我们的数据和最新发表的发现，我们提出了葡萄糖氧化的核心假设调节人类胚胎干细胞（HESC）的自我更新和分化。我们建议通过检验以下三个假设来评估这一点：在AIM 1中，我们将评估调节葡萄糖氧化对hESC代谢活性的影响。在AIM 2中，我们将评估调节葡萄糖氧化对hESC的自我更新和分化的影响。在AIM 3中，我们将评估通过使用畸胎瘤形成和血管生成的体内模型，如何增强线粒体葡萄糖氧化会影响HESC的治疗使用。该提案研究了一个新的范式，因为线粒体葡萄糖氧化与人类ESC命运之间尚未明确建立的联系。我们研究的结果可能会产生对细胞代谢和再生过程的主要见解。由于目前有多个代谢的药理调节剂，并且已被批准用于患者，因此我们认为，我们关于STEM生物学中代谢过程的发现很容易被转化为临床环境，以改善再生干细胞疗法。