Metabolic regulation in growth factor-dependent cells

描述(由申请人提供)： 这项建议勾勒出了一项全面的计划，以发展生物化学遗传学的学术生涯。这位候选人是费城儿童医院(CHOP)的儿科学讲师，接受宾夕法尼亚大学克雷格·汤普森医学博士的基础科学研究指导，以及CHOP儿童发展、康复医学和新陈代谢疾病部门医学博士马克·尤德科夫的临床指导。 儿童线粒体疾病是一种无法治愈的遗传性疾病，会扰乱脂质和其他物质的新陈代谢。它们会损害许多组织，包括骨髓，在这些组织中，细胞增殖失败会导致对感染的易感性增加。由于骨髓中的细胞依赖生长因子刺激来指导其新陈代谢，我们假设线粒体疾病阻止生长因子引发支持免疫反应的细胞增殖特性所需的代谢反应。我们建议研究生长因子如何刺激脂肪酸和脂肪的合成，因为它们必须大量产生才能使细胞增殖。我们的长期目标是了解线粒体代谢的遗传缺陷为什么会损害生长因子依赖细胞中的脂质合成，并利用这些信息来改善患有此类疾病的儿童的健康。在我们的第一个目标中，我们研究生长因子刺激Akt是如何引导脂肪酸合成的。在我们的第二个目标中，我们研究了生长因子抑制脂肪酸降解的机制和重要性。在我们的第三个目标中，我们专注于线粒体电子传输链(ETC)中损害脂质合成的缺陷。我们将建立ETC功能障碍的模型，并用它们来检验这一假说，即激活激酶AMPK会协调ETC疾病中出现的脂代谢异常。 线粒体疾病仍然是儿童智力低下、发病率和死亡率的重要来源。对这些疾病的诊断和治疗仍然不充分，部分原因是对其病理生理学的了解不完全。本文提出的研究将为了解生长因子信号、脂质生物学和线粒体代谢之间的联系提供基础，并可能为改善这些儿童的生长和免疫功能提供新的治疗途径。

DESCRIPTION (provided by applicant): This proposal outlines a comprehensive plan for the PI to develop an academic career in Biochemical Genetics. The candidate, an Instructor in Pediatrics at The Children's Hospital of Philadelphia (CHOP), receives basic science research mentoring from Craig Thompson, MD at the University of Pennsylvania, and clinical mentoring from Marc Yudkoff, MD of CHOP'S Division of Child Development, Rehabilitation Medicine and Metabolic Disease. Pediatric mitochondrial diseases are untreatable genetic disorders that disrupt metabolism of lipids and other substances. They impair many tissues, including the bone marrow, where failure of cell proliferation results in increased susceptibility to infection. Because cells in the bone marrow depend on growth factor stimulation to direct their metabolism, we hypothesize that mitochondrial diseases prevent growth factors from eliciting metabolic responses needed to support the cell proliferation characteristic of immune responses. We propose to study how growth factors stimulate synthesis of fatty acids and lipids, because they must be produced in abundance in order for cells to proliferate. Our long-term goal is to understand why genetic defects in mitochondrial metabolism impair lipid synthesis in growth factor - dependent cells, and to use this information to improve the health of children with such diseases. In our first aim, we study how growth factor stimulation of the kinase Akt directs fatty acid synthesis. In our second aim, we study the mechanism and importance of growth factor suppression of fatty acid degradation. In our third aim, we focus on defects in the mitochondrial electron transport chain (ETC) that impair lipid synthesis. We will establish models of ETC dysfunction and use them to test the hypothesis that activation of the kinase AMPK orchestrates abnormalities in lipid metabolism seen in ETC diseases. Mitochondrial diseases continue to be a significant source of mental retardation, morbidity and mortality in children. Diagnosis and treatment of these disorders continues to be inadequate, in part because of an incomplete understanding of their pathophysiology. The studies proposed here will provide a foundation to understand connections between growth factor signaling, lipid biology and mitochondrial metabolism, and could suggest new therapeutic avenues to improve growth and immune function in these children.