Metabolic regulation in growth factor-dependent cells

生长因子依赖性细胞的代谢调节

• 批准号: 7253292
• 负责人: RALPH J DEBERARDINIS
• 金额: $ 7.46万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-01-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7253292
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Address; Basic Science; Biochemical Genetics; Biology; Bone Marrow; Carnitine; Cell Proliferation; Cells; Characteristics; Child; Child Development; Child health care; Childhood; Clinical; Complex; Defect; Diagnosis; Disease; Electron Transport; Esterified Fatty Acids; Fatty Acids; Foundations; Functional disorder; Genetic Models; Glucose; Glutamine; Goals; Growth; Growth Factor; Hereditary Disease; Immune response; Immune system; Infection; Knock-out; Lipids; Lymphocyte; Mediating; Medicine; Mental Retardation; Mentors; Metabolic; Metabolic Diseases; Metabolism; Mitochondria; Mitochondrial Diseases; Modeling; Morbidity - disease rate; Mutation; Nucleic Acids; Pancytopenia; Pediatric Hospitals; Pediatrics; Pennsylvania; Philadelphia; Phospholipids; Phosphotransferases; Physiological; Post-Translational Protein Processing; Predisposition; Process; Production; Proliferating; Proteins; Regulation; Rehabilitation therapy; Research; Research Personnel; SRE-1 binding protein; Signal Transduction; Source; Stromal Cells; Supporting Cell; Testing; Tissues; Transferase; Universities; career; desaturase; fatty acid oxidation; immune function; improved; in vivo; insight; instructor; isoprenoid; lipid metabolism; lymphocyte proliferation; macromolecule; mortality; novel therapeutics; oxidation; prevent; programs; research study; response; stearoyl-coenzyme A

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.

描述（由申请人提供）： 该建议概述了PI在生化遗传学领域发展学术生涯的全面计划。这位候选人是费城儿童医院（CHOP）的儿科讲师，从宾夕法尼亚大学的医学博士Craig Thompson获得了基础科学研究指导，并获得了CHOP的儿童发展，康复医学和代谢性疾病的CHOP的Marc Yudkoff的临床指导。 小儿线粒体疾病是破坏脂质和其他物质代谢的不可治疗的遗传疾病。它们会损害许多组织，包括骨髓，在这些组织中，细胞增殖的失败会导致感染的易感性增加。因为骨髓中的细胞取决于生长因子刺激来指导其代谢，所以我们假设线粒体疾病可以防止生长因子引起支持免疫反应的细胞增殖特征所需的代谢反应。我们建议研究生长因子如何刺激脂肪酸和脂质的合成，因为它们必须大量生产才能使细胞增殖。我们的长期目标是了解为什么线粒体代谢中的遗传缺陷会损害生长因子 - 依赖性细胞中的脂质合成，并使用这些信息来改善此类疾病儿童的健康。在我们的第一个目标中，我们研究了激酶AKT的生长因子刺激如何指导脂肪酸合成。在第二个目标中，我们研究了脂肪酸降解的生长因子抑制的机制和重要性。在我们的第三个目标中，我们专注于损害脂质合成的线粒体电子传输链（ETC）的缺陷。我们将建立ETC功能障碍的模型，并使用它们来检验以下假设：激酶AMPK激活在ETC疾病中观察到的脂质代谢异常。 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。这些疾病的诊断和治疗仍然不足，部分原因是对它们的病理生理学不完全理解。这里提出的研究将为了解生长因子信号传导，脂质生物学和线粒体代谢之间的联系提供基础，并可能提出新的治疗途径，以改善这些儿童的生长和免疫功能。