ANALYSIS OF FKHRL1 INDUCED APOPTOSIS IN NEURONS

本研究的总体目标是阐明决定神经元存活和死亡的细胞机制。该提案概述了将剖析FKHRL 1-神经元生存和死亡机制的实验。该提案概述了将剖析FKHRL 1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的显性负性异构体对凋亡的影响，确定FKHRL 1在正常神经元凋亡中的作用。2)通过测定内源性FN和14 - 3-3蛋白之间的相互作用以及分析不能与14 - 3 - 3蛋白相互作用的突变FH蛋白的亚细胞定位，确定14-3 - 3蛋白在FKHRL 1细胞质定位中的作用。3)探讨FH细胞核输入输出的分子机制。阐明FKHRL 1参与神经元凋亡和理解调节FKHRL 1诱导的凋亡的机制可能导致神经退行性疾病或以生长、存活和凋亡的异常调节为特征的癌症疾病的新疗法的开发。

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.