Signaling Pathways Regulating Neuronal Survival

项目摘要：大多数神经系统疾病的一个共同特征是早产和异常 神经元的退化。参与促进或抑制神经元存活的各种分子 已经被确认了。这项提议的重点是组蛋白脱乙酰酶(HDAC)，这是一种酶家族，它可以 最近都成为了密集调查的对象。越来越多的证据表明，除了 HDAC参与多种不同的生物学过程，调节神经元的存活。目标是 这一建议的目的是更好地了解HDACs在调节神经元存活中的作用。这个 这一建议是基于我们最近的发现，与HDAC相关的蛋白质(HDRP)，一种高度 在大脑中表达，保护培养的小脑和皮质神经元免受凋亡。我们还发现， C-jun是一种蛋白质，在体内和体外的各种范例中都是神经退化所必需的 被HDRP抑制。C-jun的抑制作用是通过hdrp与c-jun氨基末端的直接相互作用来实现的。 激酶(JNK)，通过其磷酸化激活c-jun的酶。《公约》的总体目标 建议更好地了解HDRP介导的神经保护的机制，希望 开发治疗神经退行性疾病的新策略。我们提议背后的假设 HDRP通过与JNK以及其他信号蛋白的相互作用发挥作用。长期的HDRP- 缺乏会使大脑容易受到损害，而HDRP在大脑中的过度表达将保护 它来自神经毒性的侮辱。我们的具体目标之一是通过以下方式识别大脑中与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 使用各种生化和分子生物学方法进行激活。第三个目标将是 检查HDAC缺陷小鼠的大脑是否有任何异常。焦点也将被放置在 关于老年HDAC缺陷小鼠脑内病变性质的特征。第四个目标和 我们建议的最终目标是检查大脑中过度表达HDRP的转基因小鼠是否更多 在神经退行性疾病的体内实验模型中抵抗神经元丢失。 相关性：神经系统疾病扰乱了患者的生活质量，给社会造成了数十亿美元的损失 每年一次。虽然许多神经系统疾病都有对症治疗，但目前还没有治愈的方法。 可用。我们希望，我们提出的研究结果将有助于深入了解HDRP如何 防止神经元丢失，从而为治疗策略的发展提供新的靶点 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.