PTEN Anti-Oncogene Influences on Neuronal Function & Toxicity

描述(申请人提供)：PTEN抑癌基因是恶性脑瘤中最常见的突变基因之一。正常情况下，PTEN是一种脂质磷酸酶，主要通过抑制PI3Kinase/AKT通路来阻断恶性表型，但PTEN也可以作为一种蛋白磷酸酶发挥作用。PTEN在发育后期的大脑中表达，神经元的表达贯穿整个成年生活。虽然PTEN的缺失可以导致神经元的增殖，但对PTEN在神经元发育和正常神经元中的作用知之甚少。受PTEN影响的通路提示，这种抑癌基因可能增加神经元对毒性和/或退变过程的敏感性，这一点得到了我们初步数据的支持。这项提议将首先确定PTEN是否可以调节培养的神经元样细胞对阿尔茨海默病和帕金森病模型中使用的毒素的敏感性。在研究这一假说时，我们意外地发现PTEN阻断了PC12细胞中的NGF信号，这至少部分是由于在蛋白质和mRNA水平上抑制了TrkA和p75 NGF受体的表达。DNA微阵列随后发现PTEN可以抑制几个基因的表达，包括酪氨酸羟基酶和GTP环水解酶 1.由于这也可能对神经元功能和帕金森病有影响，本提案的第二个目的也将探索PTEN抑制这些基因表达的机制。这项建议的最终目的将探索在神经退行性疾病模型中使用的年龄和神经毒素对PTEN水平和功能的影响，以确定前两个目标产生的数据的生物学相关性。这些研究和我作为一名独立临床科学家的发展将得到M.Flint Beal博士的大力推动，他将担任我的赞助人，他是PD和AD中神经元变性的领先专家。埃里克·霍兰德博士是抗癌基因信号转导方面的领先专家，他的额外指导也将极大地促进我的科学成长，也将帮助我实现这项提案的许多具体目标。康奈尔大学的环境和我所在机构的大力支持将使我能够专注于这些研究，最大限度地减少分心。我的科学背景很扎实，这将有助于实现这个项目的目标。然而，该奖项中概述的这一计划将加强我以前未得到充分利用的教育方面，同时专注于一个重要的科学问题，以促进向科学独立的成功过渡。

DESCRIPTION (provided by applicant): The PTEN anti-oncogene is among the most frequently mutated genes in malignant brain tumors. Normally, PTEN is a lipid phosphatase which blocks malignant phenotypes primarily by inhibiting the PI3 Kinase/AKT pathways, but PTEN can also act as a protein phosphatase. PTEN is expressed in brain late in development, and neuronal expression continues throughout adult life. Although loss of PTEN can cause neuronal hyperplasia, little is known about the role of PTEN in neuronal development or in normal neurons. Pathways influenced by PTEN suggest that this anti-oncogene may increase neuronal sensitivity to toxicity and/or degenerative processes, which is supported by our preliminary data. This proposal will first determine whether PTEN can modulate sensitivity of cultured neuron-like cells to toxins used in models of Alzheimer's disease and Parkinson's disease. While studying this hypothesis, we have unexpectedly found that PTEN blocks NGF signaling in PC12 cells, and this appears to be at least partially due to inhibition of expression of trkA and p75 NGF receptors at the protein and mRNA levels. DNA microarray then revealed that PTEN can inhibit expression of several genes, including tyrosine hydroxylase and GTP cyclohydrolase 1. Since this may also have implications for neuronal function and for Parkinson's disease, the second Aim of this proposal will also explore the mechanism by which PTEN inhibits expression of these genes. The final Aim of this proposal will explore the effect of age and neurotoxins used in models of neurodegenerative disorders on PTEN levels and function to determine the biological relevance of data generated from the first two Aims. These studies and my development as an independent clinical scientist will be significantly advanced by Dr. M. Flint Beal, who will serve as my sponsor and who is a leading expert in neuronal degeneration in PD and AD. Additional mentoring by Dr. Eric Holland, a leading expert on anti-oncogene signal transduction, will also add significantly to my scientific growth and will also help me to realize many of the Specific Aims of this proposal. The environment at Cornell and the strong support of my institution will permit me to focus upon these studies with minimal distractions. My scientific background is substantial, and this will facilitate realization of the goal of this project. This plan outlined in this award will, however, enhance previously underserved aspects of my education while focusing on an important scientific question, in order to promote a successful transition to scientific independence.