Atg1 homologues in autophagy, mitochondrial degradation and erythroid maturation

Atg1 同源物在自噬、线粒体降解和红细胞成熟中的作用

基本信息

批准号：
7476332
负责人：
MONDIRA KUNDU
金额：
$ 13.3万
依托单位：
ST. JUDE CHILDREN'S RESEARCH HOSPITAL
依托单位国家：
美国
项目类别：
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/7476332
关键词：
3-methyladenine Acute leukemia Address Amino Acids Anemia Autophagocytosis Autophagosome Bone Marrow Cancer Biology Catabolic Process Cell Line Cell Survival Cell physiology Cells Chairperson Chemicals Clinical Complement Defect Development Dysmyelopoietic Syndromes Embryo Erythroid Erythroid Cells Erythropoiesis Foundations Genes Goals Growth Factor Hematological Disease Hematopoietic Homologous Gene Hydroxychloroquine Impairment Interleukin-3 Knowledge Laboratories Lysosomes Malignant Neoplasms Mammalian Cell Membrane Mentors Mentorship Mitochondria Molecular Mus Myopathy Nerve Degeneration Nucleotides Numbers Organelles Pathway interactions Patients Pennsylvania Play Process Production Program Development Range Reagent Recycling Regulation Research Research Personnel Reticulocytes Role Scientist Small Interfering RNA Staging Starvation System Time Training Universities Withdrawal Yeasts abstracting axon growth base career embryonic stem cell human disease inhibitor/antagonist mitochondrial autophagy programs research study response small hairpin RNA stem

项目摘要

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促红细胞生成中的作用。自噬是一种分解代谢过程，其中包括细胞体（包括细胞器）在双膜自噬体中隔离，并递送至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起着重要作用，从细胞器更新到饥饿时动员氨基酸，自噬的缺陷与包括癌症在内的许多人类疾病有关。自噬（ATG基因）所涉及的基因在酵母中的表征最好，尽管已经确定了许多哺乳动物的同源物，但尚未以它们在自噬中的作用来表征。这些基因中有ATG1的哺乳动物同源物ULK1和ULK2。 ATG1对于诱导酵母自噬至关重要。我建议使用最近在我们的实验室中开发的系统检查这些ATG1同源物在自噬和线粒体自噬中的作用。此外，我将使用从这些初步研究中获得的知识和试剂来检验以下假设：自噬有助于细胞器的降解，这是网状细胞成熟的关键步骤。骨膜成熟的末端阶段的缺陷可能导致贫血，并在骨髓增生综合征患者中观察到。该提案中概述的实验将在Craig Thompson博士的指导下进行。汤普森（Thompson）博士是宾夕法尼亚大学癌症生物学的董事长，在沿着高度生产研究职业的临床科学家指导临床科学家方面具有广泛的记录。这项职业发展计划将补充我作为血液病理学家的临床培训，并将为启动独立的学术职业奠定基础，该职业生涯研究正常的红斑发育及其与血液学疾病的关系，包括骨髓增生性综合征和急性白血病。（抽象的结尾）