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Fundamental mechanisms of apoptosis and phospholipid asymmetry

细胞凋亡和磷脂不对称的基本机制

基本信息

批准号：
10084175
负责人：
DING XUE
金额：
$ 2.1万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-01 至 2021-05-31
项目状态：
已结题

项目摘要

Project summary Programmed cell death, phospholipid asymmetry, and paternal mitochondrial elimination are three vitally important, distinct, and interconnected biological processes essential for normal cell functions and animal development. Defects in these processes can cause various pathological conditions and human disease, including neurodegenerative disease, autoimmune disorders, various inherited human mitochondrial disease, and cancer. In this proposed work, we will carry out molecular genetic, reverse genetic, biochemical, cell biological, biophysical, and functional genomic analyses to decipher basic mechanisms of apoptosis, phospholipid asymmetry, and paternal mitochondrial elimination during animal development. For the study of apoptosis, we hope to understand the regulatory mechanisms and signaling pathways that control the release of mitochondrial apoptogenic factors during apoptosis and identify new targets and downstream pathways of the cell death protease that execute highly organized cell disassembly and rapid removal of the dying cells. For the study of phospholipid asymmetry, we plan to identify the molecular components and regulatory machineries that generate, maintain, and alter phospholipid asymmetry, decipher the functions and roles of specific phospholipids to a cell, and reveal the physiological and pathological consequences of altered phospholipid asymmetry to the cell and the animal. For the study of paternal mitochondrial elimination, we will investigate how and why paternal mitochondria are selectively recognized and targeted for elimination, the paternal and maternal factors and machineries required of this uniparental inheritance process, and the physiological significance of paternal mitochondrial elimination to embryo development and organismal fitness. These studies should reveal novel mechanisms, pathways, and genes that control these three fundamental biological processes, and ultimately, provide new targets, ideas, and strategies to facilitate treatment of numerous human diseases caused by abnormalities in these three important processes.

项目摘要细胞程序性死亡、磷脂不对称和父源性线粒体消除是三个重要的重要的，独特的和相互关联的生物过程，对正常细胞功能和动物发展这些过程中的缺陷可导致各种病理状况和人类疾病，包括神经变性疾病、自身免疫性疾病、各种遗传性人线粒体疾病和癌症在这项拟议的工作中，我们将进行分子遗传学，反向遗传学，生物化学，细胞生物学、生物物理学和功能基因组分析，以破译细胞凋亡的基本机制，磷脂不对称性和动物发育过程中父系线粒体的消除。为研究细胞凋亡，我们希望了解调控机制和信号通路，控制释放线粒体促凋亡因子在凋亡过程中的作用，并确定新的靶点和下游途径，该细胞死亡蛋白酶执行高度有组织的细胞分解和快速去除垂死细胞。为磷脂不对称性的研究，我们计划确定分子组成和调节产生、维持和改变磷脂不对称性的机制，具体磷脂的细胞，并揭示生理和病理后果的改变磷脂不对称性对细胞和动物的影响。对于父系线粒体消除的研究，我们将研究如何以及为什么选择性地识别和消除父系线粒体，父亲和母亲的因素和机器所需的这一单亲遗传过程，和父系线粒体消除对胚胎发育和生物体适应性的生理意义。这些研究应该揭示新的机制，途径和基因，控制这三个基本的生物过程，并最终提供新的目标，想法和策略，以促进治疗这三个重要过程的异常导致了人类的许多疾病。