Atg 1homologues in autophagy, mitochondrial degradation

自噬、线粒体降解中的 Atg 1 同系物

• 批准号: 7082706
• 负责人: MONDIRA KUNDU
• 金额: $ 13.3万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7082706
• 关键词: Friend virus; antibody; autophagy; biological signal transduction; biotransformation; cell differentiation; cell line; chloroquine; embryonic stem cell; enzyme activity; enzyme induction /repression; erythropoiesis; genetic regulation; genetically modified animals; immunofluorescence technique; laboratory mouse; lipoxygenase; mitochondria; polymerase chain reaction; protein localization; reticulocytes; serine threonine protein kinase

DESCRIPTION (provided by applicant): The long-term goals of this study are to understand the molecular basis of autophagy and its role in erythropoiesis. Autophagy is a catabolic process in which cytosolic components, including organelles, are sequestered in double-membrane autophagosomes and delivered to the lysosome for degradation and recycling of essential components (amino acids, nucleotides, etc). Autophagy plays important roles in regulating a range of cellular processes, from organelle turnover to the mobilization of amino acids upon starvation, and defects in autophagy have been associated with a number of human diseases including cancer. The genes involved in autophagy (Atg genes) have been best characterized in yeast and although the many of the mammalian homologues have been identified have not been characterized in terms of their roles in autophagy. Among these genes are Ulk1 and Ulk2, the mammalian homologues of Atg1. Atg1 is critical for the induction of autophagy in yeast. I propose to examine the role of these Atg1 homologues in autophagy and mitochondrial autophagy will be examined using a system that has recently been developed in our laboratory. In addition, I will use the knowledge and reagents gained from these initial studies will be used to examine the hypothesis that autophagy contributes to the degradation of organelles that is a critical step in reticulocyte maturation. Defects in the terminal stage of erythroid maturation may result in anemia and have been observed in patients with myelodysplastic syndrome. The experiments outlined in this proposal will be conducted under the mentorship of Dr. Craig Thompson. Dr. Thompson is the Chairman of Cancer Biology at the University of Pennsylvania and has an extensive track record in mentoring clinical scientists along the path to highly production research careers. This career development program will complement my clinical training as a hematopathologist and will provide the foundation for launching an independent academic career studying normal erythroid development and its relationship to hematological disorders, including myelodysplastic syndromes and acute leukemias. (End of Abstract)

描述（由申请人提供）： 这项研究的长期目标是了解自噬的分子基础及其在红细胞生成中的作用。自噬是一种分解代谢过程，其中包括细胞器在内的胞质成分被隔离在双膜自噬体中，并被输送到溶酶体以降解和回收必需成分（氨基酸、核苷酸等）。自噬在调节一系列细胞过程中发挥着重要作用，从细胞器更新到饥饿时氨基酸的动员，自噬缺陷与包括癌症在内的许多人类疾病有关。参与自噬的基因（Atg 基因）在酵母中得到了最好的表征，尽管已鉴定出许多哺乳动物同源物，但尚未对其在自噬中的作用进行表征。这些基因包括 Ulk1 和 Ulk2，它们是 Atg1 的哺乳动物同源物。 Atg1 对于酵母自噬的诱导至关重要。我建议研究这些 Atg1 同源物在自噬中的作用，并且将使用我们实验室最近开发的系统来检查线粒体自噬。此外，我将利用从这些初步研究中获得的知识和试剂来检验自噬导致细胞器降解的假设，而细胞器降解是网织红细胞成熟的关键步骤。红细胞成熟末期的缺陷可能导致贫血，并且已在骨髓增生异常综合征患者中观察到。本提案中概述的实验将在克雷格·汤普森博士的指导下进行。 Thompson 博士是宾夕法尼亚大学癌症生物学系主任，在指导临床科学家走向高产研究职业道路方面拥有丰富的经验。该职业发展计划将补充我作为血液病理学家的临床培训，并将为开展独立的学术职业奠定基础，研究正常红细胞发育及其与血液疾病（包括骨髓增生异常综合征和急性白血病）的关系。 （摘要完）