Signaling Pathways Regulating Neuronal Survival

项目概述：大多数神经系统疾病的一个共同特点是过早和异常的 神经元的退化。参与促进或抑制神经元存活的多种分子 已经被确认。该提案集中于组蛋白脱乙酰酶（HDAC），这是一个酶家族， 最近成为了调查的重点越来越多的证据表明，此外， HDAC参与多种不同的生物过程，调节神经元存活。目标 这项建议的目的是更好地了解HDAC在神经元存活调节中的作用。的 这项提议是基于我们最近的发现，HDAC相关蛋白（HDRP），一种高度依赖于 在脑中表达，保护培养的小脑和皮质神经元免于凋亡。我们还发现 c-jun是一种在多种体内和体外范例中神经变性所必需的蛋白质， 被HDRP抑制。c-jun的抑制作用是通过HDRP与c-jun N-末端的直接相互作用而介导的 激酶（JNK），通过其磷酸化激活c-jun的酶。的总体目标 我们的建议是更好地理解HDRP介导的神经保护机制， 开发治疗神经退行性病变的新策略。我们提议的假设 HDRP通过与JNK以及其他信号蛋白相互作用而起作用。长期人类发展报告项目- 缺乏将使大脑容易受到损害，而大脑中HDRP的过度表达将保护大脑。 神经毒素的伤害我们的具体目标之一是通过以下方式确定大脑中HDRP相互作用的蛋白质： 酵母双杂交筛选。这些相互作用的蛋白质在HDRP介导的神经保护中的作用将 然后被研究。另一个目标是研究HDRP和JNK之间的相互作用如何抑制c-jun 使用多种生物化学和分子生物学方法活化。第三个目标是 检查HDAC缺陷小鼠的大脑是否有任何异常。重点也将放在 描述老年HDAC缺陷小鼠脑内病变的性质。第四个目标， 我们计划的最终目标是检测在大脑中过度表达HDRP的转基因小鼠是否比正常小鼠更能表达HDRP。 在神经退行性疾病的体内实验模型中对神经元损失具有抗性。 相关性：神经系统疾病破坏了患者的生活质量，并使社会损失数十亿美元 每年。虽然对症治疗可用于许多神经系统疾病，但目前还没有治愈方法。 available.我们希望，我们提出的研究结果将有助于深入了解HDRP如何 防止神经元损失，从而为治疗策略的开发提供新的靶点。 神经退行性病变

PROJECT SUMMARY: A common feature of most neurological diseases is the premature and aberrant degeneration of neurons. A variety of molecules involved in the promotion or inhibition of neuronal survival have been identified. This proposal focuses on histone deacetylases (HDACs),a family of enzymes that have become the subject of intense investigation recently. Accumulating evidence suggests that in addition to their involvement in a variety of different biological processes, HDACs regulate neuronal survival. The goal of this proposal is to better understand the role of HDACs in the regulation of neuronal survival. The proposal is based on our recent finding that HDAC-relatedprotein (HDRP), an HDAC that is highly expressed in the brain, protects cultured cerebellar and cortical neurons from apoptosis. We also found that c-jun, a protein that is necessary for neurodegeneration in a variety of in vivo and in vitro paradigms is inhibited by HDRP. The inhibition of c-jun is mediated by the direct interaction of HDRPwith c-jun N-terminal kinase (JNK), the enzyme that activates c-jun through its phosphorylation. The overall objective of the proposal is to better undertand the mechanism underlying HDRP-mediated neuroprotection in the hope of developing novel strategies to treat neurodegenerative pathologies. The hypothesis underlying our proposal is that HDRP acts through interaction with JNK, as well as other signaling proteins. Long-term HDRP- deficiency will render the brain vulnerable to damage while overexpression of HDRP in the brain will protect it from neurotoxic insults. One of our specific goals is identify HDRP-interacting proteins in the brain by yeast-two hybrid screening. The role of these interacting proteins in HDRP-mediated neuroprotection will then be studied. Another goal will be to examine how the interaction between HDRP and JNK inhibits c-jun activation using a variety of biochemical and molecular biological approaches. A third goal will be to to examine whether the brains of HDAC-deficient mice possess any abnormalities. Focus will also be placed on characterizing the nature of lesions within the brains of older HDAC-deficient mice. The fourth goal and final goal of our proposal is to examine whether transgenic mice overexpressing HDRP in the brain are more resistant to neuronal loss in an in vivo experimental model of neurodegenerative disease. RELEVANCE: Neurological diseases disrupt the quality of life for patients and cost society billions of dollars annually. While symptomatic treatments are available for many neurological diseases, a cure is not presently available. It is our hope that the results from the studies we propose will shed insight into how HDRP prevents neuronal loss and thus provide novel targets for the development of strategies to treat neurodegenerative pathologies.