ANALYSIS OF FKHRL1 INDUCED APOPTOSIS IN NEURONS

所提出的研究的总体目标是阐明控制神经元生存和死亡决定的细胞机制。该提案概述了将剖析fkhrl1神经元存活和死亡机制的实验。该提案概述了将解剖fkhrl1诱导神经元凋亡机制的实验。本研究的目的是：1)通过分析FH显性阴性亚型对正常神经元凋亡的影响，确定FKHRL1在正常神经元凋亡中的作用。2)通过分析内源性FN与14-3-3蛋白的相互作用，以及分析无法与14-3-3蛋白相互作用的突变型FH蛋白的亚细胞定位，确定14-3-3蛋白在FKHRL1胞质定位中的作用。3)确定FH核进出口的分子机制。阐明FKHRL1在神经元凋亡中的作用，了解FKHRL1诱导的细胞凋亡的调控机制，有助于开发以生长、存活和细胞凋亡异常调节为特征的神经退行性疾病或癌症疾病的新疗法。

DESCRIPTION The overall goal of the proposed research is to elucidate the cellular mechanisms that govern decisions of neuronal survival and death. The proposal outlines experiments that will dissect the mechanisms of FKHRL1-neuronal survival and death. The proposal outlines experiments that will dissect the mechanisms of FKHRL1-induced apoptosis in neurons. The aims of the proposal are: 1) To determine the role of FKHRL1 in normal neuronal apoptosis by analyzing the effects of dominant negative isoforms on FH on apoptosis. 2) To determine the role of 14-3-3 proteins in the cytoplasmic localization of FKHRL1 by assaying for interactions between endogenous FN and 14-3-3 proteins and by analyzing the subcellular localization of mutant FH proteins that are unable to interact with 14-3-3 proteins. 3) To determine the molecular mechanisms for nuclear import and export of FH. Elucidating the involvement of FKHRL1 in neuronal apoptosis and understanding the mechanisms that regulate FKHRL1-induced apoptosis could lead to development of new therapeutics for neurodegenerative diseases or cancer-diseases characterized by abnormal regulation of growth, survival and apoptosis.