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Metabolic Regulation of Myofibroblast Differentiation

Metabolic Regulation of Myofibroblast Differentiation
肌成纤维细胞分化的代谢调节
批准号:
10586076
负责人:
Robert Brian Hamanaka
金额:
$40.5万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-04-01 至 2025-03-31

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中文摘要
翻译
特发性肺纤维化(IPF)是一种致命的疾病,中位生存期为3.5年,并影响 在美国大约有89,000人。目前尚不清楚IPF的遗传原因,因此 识别疾病发病机制所需的新机制对于 开发新的治疗策略。IPF的一个明显特征是肺成纤维细胞分化为 肌成纤维细胞,分泌过量的细胞外基质(胶原),是主要细胞 对IPF的结构重塑和肺功能损害负责。我们有 最近发现,肌成纤维细胞依赖于以水平升高为特征的代谢重新编程 糖酵解和代谢产物流量通过从头开始的丝氨酸,甘氨酸,一碳(SGOC)途径促进 生产甘氨酸,用于合成胶原蛋白。甘氨酸占胶原蛋白中所有氨基酸的三分之一 从葡萄糖合成甘氨酸需要蛋白质和从头合成来支持胶原蛋白的合成 肌成纤维细胞。然而,这种代谢重新编程的信号和转录调节因子 成纤维细胞是未知的。这项提案的中心目标是确定新陈代谢的调节因素 肌成纤维细胞的重编程,并确定它们在肺纤维化中的作用。这一目标的前提是 阐明肌成纤维细胞代谢调节的机制将揭开实现 IPF中严重未得到满足的治疗需求。我们的初步结果表明,转化生长因子-β(转化生长 因子-β,参与纤维化的关键细胞因子),通过mTOR途径促进信号传递,这是 激活ATF4(激活转录因子4)。SGOC途径的表达需要ATF4 肌成纤维细胞中的酶。我们进一步表明,SGOC途径的激活不仅促进胶原蛋白 由肌成纤维细胞产生,但改变了这些细胞的表观基因组,可能提供了额外的途径 靶向肌成纤维细胞生物学用于治疗目的。在目前的提案中,我们的目标是确定 肌成纤维细胞代谢的调节剂,并确定改变代谢的机制 有助于肌成纤维细胞的表型。在特定的目标1中,我们将确定转录因子如何 ATF4在体外和体内调节肺成纤维细胞的SGOC等代谢途径。以特定的目标 2,我们将确定mTOR信号通路如何调节ATF4和其他转录调节因子 肺成纤维细胞在体内外的细胞代谢。在具体目标3中,我们将确定国家奥委会如何 体内和体外肺成纤维细胞的表观遗传学改变与通路激活有关。我们的建议 实验将确定和充分描述纤维化形成所需的多个靶向通路。
英文摘要
Idiopathic Pulmonary Fibrosis (IPF) is a fatal disease which has a median survival of 3.5 years and affects approximately 89,000 people in the United States. There is no known genetic cause of IPF, and thus identification of new mechanisms required for disease pathogenesis is of critical importance for the development of novel treatment strategies. A defining feature of IPF is the differentiation of lung fibroblasts into myofibroblasts, which secrete excessive amounts of extracellular matrix (collagen) and are the primary cell responsible for the structural remodeling and impairment of lung function characteristic of IPF. We have recently discovered that myofibroblasts depend on metabolic reprogramming characterized by increased levels of glycolysis and metabolite flux through the de novo serine, glycine, one-carbon (SGOC) pathway to promote glycine production for collagen protein synthesis. Glycine constitutes one third of all amino acids in collagen protein and de novo synthesis of glycine from glucose is required to support collagen protein synthesis by myofibroblasts. However, the signaling and transcriptional regulators of this metabolic reprogramming in fibroblasts are unknown. The central goal of this proposal is to identify the regulators of metabolic reprogramming in myofibroblasts and to determine their role in lung fibrosis. The premise underlying this goal is that elucidating the mechanisms of metabolic regulation in myofibroblasts will unveil new strategies to fulfill the sorely unmet therapeutic need in IPF. Our preliminary results show that TGF-β (Transforming Growth Factor-β, the key cytokine involved in fibrosis), promotes signaling through the mTOR pathway, which activates ATF4 (activating transcription factor 4). ATF4 is required for the expression of SGOC pathway enzymes in myofibroblasts. We further show that SGOC pathway activation not only promotes collagen protein production by myofibroblasts, but alters the epigenome of these cells, possibly providing additional ways to target myofibroblast biology for therapeutic purposes. In the current proposal, we aim to determine the regulators of myofibroblast metabolism and determine the mechanisms by which altered metabolism contributes to the myofibroblastic phenotype. In Specific Aim 1 we will determine how the transcription factor ATF4 regulates the SGOC and other metabolic pathways in lung fibroblasts in vitro and in vivo. In Specific Aim 2, we will determine how the mTOR signaling pathway regulates ATF4 and other transcriptional regulators of cellular metabolism in lung fibroblasts in vitro and in vivo. In Specific Aim 3, we will determine how SGOC pathway activation contributes to epigenetic changes in lung fibroblasts in vitro and in vivo. Our proposed experiments will identify and fully characterize multiple targetable pathways required for fibrogenesis.
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Metabolic Regulation of Myofibroblast Differentiation
  • 批准号:
    10372121
  • 项目类别:
  • 资助金额:
    $40.5万
  • 财政年份:
    2020
  • 负责人:
    Robert Brian Hamanaka
  • 依托单位:
Metabolic Regulation of Epidermal Homeostasis
  • 批准号:
    8750649
  • 项目类别:
  • 资助金额:
    $8.48万
  • 财政年份:
    2014
  • 负责人:
    Robert Brian Hamanaka
  • 依托单位:
Metabolic Regulation of Epidermal Homeostasis
  • 批准号:
    8918418
  • 项目类别:
  • 资助金额:
    $8.48万
  • 财政年份:
    2014
  • 负责人:
    Robert Brian Hamanaka
  • 依托单位:
Metabolic Regulation of Epidermal Homeostasis
  • 批准号:
    9115906
  • 项目类别:
  • 资助金额:
    $8.48万
  • 财政年份:
    2014
  • 负责人:
    Robert Brian Hamanaka
  • 依托单位:
海外基金