Fundamental mechanisms of apoptosis and phospholipid asymmetry

项目总结 细胞程序性死亡、磷脂不对称和父本线粒体消除是三个至关重要的因素 对正常细胞功能和动物至关重要的重要的、不同的和相互关联的生物过程 发展。这些过程中的缺陷会导致各种病理情况和人类疾病， 包括神经退行性疾病，自身免疫性疾病，各种遗传性人类线粒体疾病， 和癌症。在这项拟议的工作中，我们将进行分子遗传、反向遗传、生化、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，以及动物发育过程中父系线粒体的消除。为了研究 凋亡，我们希望了解控制释放的调节机制和信号通路 细胞凋亡过程中线粒体致凋亡因子的变化，并确定新的靶点和下游途径 执行高度组织化的细胞分解和快速去除死亡细胞的细胞死亡蛋白。为 在磷脂不对称性的研究中，我们计划确定其分子组成和调控 产生、维持和改变磷脂不对称的机制，破译磷脂的功能和角色 特定的磷脂到细胞，并揭示改变的生理和病理后果 磷脂对细胞和动物的不对称性。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亲的线粒体， 父亲和母亲的因素和单亲遗传过程所需的机制，以及 父系线粒体消除对胚胎发育和机体健康的生理意义。 这些研究应该揭示控制这三个基本因素的新机制、途径和基因 生物过程，并最终提供新的靶点，想法和战略，以促进治疗 由这三个重要过程中的异常引起的人类疾病不胜枚举。

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.