HDACs in Neurodegeneration and Aging

与癌症相关的疾病可以说是21世纪生物医学面临的最大挑战。 年龄是一系列疾病的最大单一风险因素，包括心血管功能障碍、癌症、 II型糖尿病、骨质疏松症和神经变性。延缓（或降低）衰老将 延缓多种与年龄有关的疾病的进程，从而大大增加平均健康寿命。 我们开发合理方法来预防或干预衰老的能力关键取决于 深入了解导致衰老的基本机制，以及特定年龄相关疾病的病因 疾病我们认为，特别是在生物医学领域， 这种方法将加速发现，并为治疗干预提供合理的途径。从长远 这将导致建立一个综合性的新学科，即“老年科学”。"尽管 在简单的生物体中，我们已经识别出了100多个决定寿命的基因，但我们对这些基因还没有真正的了解。 这些基因是如何影响衰老和疾病的这部分是因为大多数研究都是在 通过观察衰老的基本生物学或单独观察这些已识别基因的影响来进行隔离 关于疾病在这项与U54具体目标1直接相关的提案中，具体目标1。到 建立一个关于衰老与疾病关系的跨学科研究计划，重点是 神经退行性疾病和癌症，我们将在三个神经退行性疾病模型， 亨廷顿氏病-Ellerby博士（组分7）、Hughes博士（组分6）、Nicholls博士和吉布森 帕金森病-安德森博士（组分9）和阿尔茨海默病-安德森博士（组分11）。 Bredesen（组分1）和模式生物C. elegans-Dr. Kapahi（组件2）-的作用 组蛋白脱乙酰酶（HDACs）在神经退行性变和衰老中的作用。这是一个重要的领域， 近年来，研究人员在神经退行性疾病方面取得了一系列重要发现， 在衰老中，这些酶（HDAC）在神经变性或衰老中起主要作用。然而，在这方面， 研究人员还没有解剖出哺乳动物系统中哪些家族成员是关键的目标 防止神经退化和衰老。这些项目的一个中心主题是， 是决定疾病的关键因素。药物的目标是维持 这些监管机构的职能或加强其职能将是拟议干预措施的重要目标。 我们的假设是，受损的乙酰化体内平衡是直接耦合到 神经变性和鉴定参与该过程的特定HDAC家族成员 将确定对神经退化和衰老至关重要的治疗靶点。

Age-related disease is arguably the single greatest challenge for biomedicine in the 21st Century. Age is the largest single risk factor for a panoply of diseases, including cardiovascular dysfunction, cancer, type II diabetes, osteoporosis, and neurodegeneration. Postponing (or decreasing the rate of) aging would retard the course of multiple age-related diseases and therefore substantially increase average health-span. Our ability to develop rational approaches to preventing or intervening in aging depends crucially on a thorough understanding of the basic mechanisms that cause aging, as well as the etiology of specific agerelated diseases. We believe that it is especially in this area of biomedicine where an interdisciplinary approach will accelerate discoveries and provide rational avenues for therapeutic intervention. In the long term this will lead to the establishment of a comprehensive new discipline, that of "Geroscience." Despite having identified 100s of genes that determine lifespan in simple organisms, we have no true understanding of how these genes are impacting on aging and disease. This is in part that most studies are carried in isolation by either looking at the basic biology of aging or separately at the impact of these identified genes on disease. In this proposal, which is directly relevant to Specfic Aim 1 of the U54, Specific Aim 1. To establish an interdisciplinary research program on the aging-disease relationship with a focus on neurodegeneration and cancer, we will address across three neurodegenerative disease models, Huntington's disease-Dr. Ellerby (Component 7), Dr. Hughes (Component 6), Dr. Nicholls and Gibson (Component 11), Parkinson's disease-Dr. Andersen (Component 9) and Alzheimer's disease-Dr. Bredesen (Component 1), and the model organism C. elegans-Dr. Kapahi (Component 2)- the role of histone deacetylase (HDACs) in neurodegeneration and aging. This represents a significant area as researchers have made a series of important discoveries in recent years on neurodegenerative disease and in aging that these enzymes (HDACs) play a major in role in neurodegeneration or aging. However, researchers have not yet dissected out in mammalian systems which family members are critical to target to prevent neurodegeneration and aging. A central theme of these projects is the notion that genes that are known to modulate aging are key factors in determining disease. Drugs that target the maintenance functions of these regulators or enhance their function will be important targets for proposed interventions. Our hypothesis is that compromised acetylation homoeostasis is directed coupled to neurodegeneration and identification of particular HDACs family members involved in this process will identify therapeutic targets critical to neurodegeneration and aging.