PTEN Anti-Oncogene: Neuronal Function and Toxicity

PTEN 抗癌基因：神经元功能和毒性

• 批准号: 6821785
• 负责人: MICHAEL G KAPLITT
• 金额: $ 14.58万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6821785
• 关键词: Alzheimer' s disease; PC12 cells; Parkinson' s disease; aging; animal old age; apoptosis; biological signal transduction; cell growth regulation; cytotoxicity; disease /disorder model; gene expression; genetic regulation; genetically modified animals; hydrolase; juvenile animal; laboratory mouse; neural degeneration; neurogenetics; neuropathology; neuroregulation; neurotoxicology; neurotoxins; phosphoprotein phosphatase; protein structure function; tumor suppressor proteins

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.

描述（由申请人提供）：PTEN抗癌基因是恶性脑肿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PI3激酶/AKT通路来阻断恶性表型，但PTEN也可以作为一种蛋白磷酸酶。PTEN在发育后期在大脑中表达，并且在整个成年期神经元中持续表达。尽管PTEN的缺失可导致神经元增生，但对于PTEN在神经元发育或正常神经元中的作用知之甚少。受PTEN影响的通路表明，这种抗癌基因可能增加神经元对毒性和/或退行性过程的敏感性，我们的初步数据支持这一点。该方案将首先确定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。在研究这一假设时，我们意外地发现PTEN在PC12细胞中阻断NGF信号传导，这似乎至少部分是由于在蛋白和mRNA水平上抑制trkA和p75 NGF受体的表达。DNA芯片显示，PTEN可以抑制酪氨酸羟化酶和GTP环水解酶等基因的表达