Fundamental mechanisms of apoptosis and phospholipid asymmetry

 描述(由申请人提供)：程序性细胞死亡和磷脂不对称是两个极其重要、截然不同且相互关联的生物学过程，对正常细胞功能和动物发育至关重要。这两个过程中的缺陷会导致各种病理状况和人类疾病，包括神经退行性疾病、自身免疫性疾病和癌症。在这项拟议的工作中，我们将进行分子遗传学、反向遗传学、生化、细胞生物学、生物物理学和功能基因组分析，以破译动物发育过程中调节细胞凋亡和磷脂不对称的基本机制。对于细胞凋亡的研究，我们希望了解在细胞凋亡过程中控制线粒体致凋亡因子释放的调控机制和信号通路，并识别执行高度组织化的细胞分解和快速去除濒死细胞的细胞死亡蛋白酶的新靶点和下游途径。对于磷脂不对称性的研究，我们计划确定产生、维持和改变磷脂不对称性的分子组成和调节机制，重点是了解磷脂酰丝氨酸(PS)的不对称性。我们将破译特定磷脂对细胞的功能和作用，并揭示改变磷脂不对称对细胞和动物的生理和病理后果。这些研究将揭示控制这两个基本生物过程的新机制、途径和基因，并最终提供新的靶点、想法和策略，以促进由这两个重要过程中的异常引起的许多人类疾病的治疗。

 DESCRIPTION (provided by applicant): Programmed cell death and phospholipid asymmetry are two vitally important, distinct, and interconnected biological processes essential for normal cell functions and animal development. Defects in these two processes can cause various pathological conditions and human disease, including neurodegenerative disease, autoimmune disorders, 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 that regulate apoptosis and phospholipid asymmetry 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 proteases 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, focusing on understanding phosphatidylserine (PS) asymmetry. We will 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 animals. These studies should reveal novel mechanisms, pathways, and genes that control these two fundamental biological processes, and ultimately, provide new targets, ideas, and strategies to facilitate treatment of numerous human diseases caused by abnormalities in these two important processes.