p66Shc mediated effects on ROS signaling and cytoskeletal remodeling

哺乳动物细胞使用称为线粒体的专门细胞器来分解营养物质并产生高水平的ATP，这是一种化学形式的能量。 为了产生ATP，线粒体消耗氧气，同时产生二氧化碳和水。 氧自由基是线粒体代谢过程中产生的潜在有害副产物。 在衰老过程中，哺乳动物经常表现出氧自由基产生增加，或解毒能力下降，特别是在称为神经元的专门脑细胞中。 随着年龄的增长，线粒体自由基产生增加的机制知之甚少。 有趣的是，小鼠中p66Shc基因的缺失导致对氧化剂暴露的耐受性增加和寿命延长。 最近的研究表明，p66Shc蛋白可以从胞质溶胶（细胞的主要流体包含部分细胞）进入线粒体，暴露于某些形式的应激后。 一旦进入线粒体，p66Shc触发氧自由基形成增加，从而促进一系列变化，包括细胞形状、运动的改变，以及在某些情况下的细胞死亡。 这些观察结果表明，p66 Shc是氧自由基产生，氧化剂敏感性，细胞形态和有机体衰老的主要调节剂。 然而，p66Shc控制这些过程的确切机制知之甚少。 使用在我的实验室开发的各种新技术，我们将探讨假设p66Shc诱导的氧自由基的产生在培养的神经元细胞系导致特定的蛋白质，控制细胞形态，运动和信号转导过程的氧化。 我们认为，这些蛋白质的氧化导致蛋白质活性改变，并随着年龄的增长而损害神经元功能。 这项研究的结果将为控制神经元衰老过程的分子机制提供新的见解。

Mammalian cells used specialized organelles called mitochondria to break down nutrients and generate high levels of ATP, a chemical form of energy. In order to generate ATP, mitochondria consume oxygen while at the same time producing carbon dioxide and water. Oxygen radicals are potentially harmful by-products that arise during mitochondrial metabolism. During the aging process, mammals frequently exhibit increased production of oxygen radicals, or the decreased ability to detoxify them, particularly in specialized brain cells called neurons. The mechanism responsible for increased mitochondrial radical production that occurs with age is poorly understood. Interestingly, loss of the p66Shc gene in mice results in increased tolerance to oxidant exposure and extended lifespan. Recent studies have shown that the p66Shc protein can move from the cytosol, the main fluid containing portion of a cell, into mitochondria following exposure to certain forms of stress. Once in the mitochondria, p66Shc triggers increased oxygen radical formation thereby promoting a series of changes including alterations in cell shape, movement and, in certain circumstances, cell death. These observations indicate that p66Shc is a major regulator of oxygen radical production, oxidant sensitivity, cell morphology and organismal aging. However the precise mechanism by which p66Shc controls these processes is poorly understood. Using a variety of novel techniques developed in my lab we will explore the hypothesis that p66Shc induced oxygen radical production in cultured neuronal cell lines leads to oxidation of specific proteins which control cell morphology, movement and signaling processes. We believe that oxidation of these proteins lead to altered protein activity and compromised neuronal function with age. The results of the proposed study will provide novel insight into the molecular mechanisms controlling the aging process in neurons.