Klotho regulation and aging

Klotho 调节和衰老

基本信息

批准号：
7770294
负责人：
Gwendalyn DiAnn King
金额：
$ 8.37万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-30 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7770294
关键词：
3&apos Untranslated Regions Accounting Affect Age Age-Months Aging Aging-Related Process Animals Atherosclerosis Atrophic condition of skin Binding Binding Sites Bone Density Brain Brain Injuries Brain Part Cell physiology Cells Cessation of life Deterioration Development Disease Down-Regulation Elements Gene Expression Gene Expression Regulation Genes Genetic Transcription Genetic Translation Guanine + Cytosine Composition Hair Human Impaired cognition Impairment In Vitro Infertility Knowledge Lead Life Light Longevity Macaca mulatta Metabolism MicroRNAs Modeling Molecular Mus Mutant Strains Mice Neurodegenerative Disorders Neurons Normal Cell Organ Osteoporosis Oxidative Stress Pathway interactions Phenotype Population Predisposition Process Proteins Pulmonary Emphysema Rattus Reactive Oxygen Species Regulation Resistance Rodent Role SP1 gene Sampling Signal Pathway Time Transcription Initiation Transgenic Mice Translations Work age effect age group age related aged aging brain aging gene aging population anti aging biological adaptation to stress calcification klotho protein long term memory mRNA Stability memory retention nonhuman primate normal aging novel overexpression oxidation oxidative damage pathological aging prevent promoter public health relevance response therapeutic development transcription factor

项目摘要

DESCRIPTION (provided by applicant): The focus of our study is to examine how the age suppressor protein, Klotho, is regulated with aging in the brain. When Klotho expression is eliminated, mice develop normally, but age to death by 4 months of age. This rapid deterioration is accompanied with a phenotype not unlike what is observed in aged humans (cognitive impairment, atherosclerosis, ectopic calcification, emphysema, osteoporosis, skin atrophy and hair loss, thymic involution, infertility and decreased bone mineral density). Elimination of Klotho in mice causes cognitive impairment that is associated with increased oxidative stress. In contrast, Klotho overexpressing transgenic mice live longer by up to 30% and are resistant to oxidative stress. Our group found that Klotho is downregulated in the aging non-human primate, rat and mouse brains Together, these have lead us to hypothesize that Klotho is important in brain function and its downregulation with age may be the result of oxidative stress which, if prevented, could ameliorate decline into neurodegenerative disease. The work proposed, examines regulation of the Klotho promoter and 3'UTR with age and the effect of oxidative damage to the Klotho promoter with age. We will determine whether the high GC content of the Klotho promoter makes it a target for age-related downregulation because of damage that accumulates over time because of oxidative stress. This will be done by comparing the oxidation state of the Klotho promoter to that of other genes both in vitro and in post mortem samples from aged rhesus monkey brain. We will also work to characterize the transcription factors that bind and induce activation of the Klotho promoter. The Klotho promoter does not contain the classical elements for transcription initiation. Understanding what factors are important for Klotho transcription may shed light on signaling pathways leading to Klotho activation and the role of Klotho in the normal cell. Last, we will determine whether Klotho is regulated by microRNAs (miR) and how miR change in the brain with age. MiR bind and regulate translation of mRNA and nothing is known about whether and how miR affect Klotho processing. Again, understanding the processes that regulate Klotho will enable us to have a better understanding of the processes that affect Klotho and Klotho's wider role in cellular function. The results of this work will add new knowledge on both the anti-aging gene Klotho and elucidate a possible mechanism for how oxidative damage selectively downregulates specific genes. PUBLIC HEALTH RELEVANCE: With a rapidly aging population, increases in age related disorders are anticipated to rise to unprecedented levels in the next 50 years. Understanding the regulation of genes known to effect and be affected by the aging process is critical to developing novel therapies for a range of disorders. The aging suppressor protein, Klotho is decreased in the brain with age and may be a target for therapeutic development against neurodegenerative disorders.

描述（由申请人提供）：我们研究的重点是检查年龄抑制蛋白 Klotho 如何随着大脑的衰老而受到调节。当 Klotho 表达被消除时，小鼠发育正常，但会在 4 个月大时死亡。这种快速恶化伴随着与老年人相似的表型（认知障碍、动脉粥样硬化、异位钙化、肺气肿、骨质疏松、皮肤萎缩和脱发、胸腺退化、不孕和骨矿物质密度降低）。消除小鼠体内的 Klotho 会导致认知障碍，而认知障碍与氧化应激增加有关。相比之下，Klotho 过度表达的转基因小鼠寿命延长了 30%，并且能够抵抗氧化应激。我们的研究小组发现，Klotho 在衰老的非人类灵长类动物、大鼠和小鼠大脑中表达下调。综合起来，这些使我们推测 Klotho 对大脑功能很重要，并且它随年龄的下调可能是氧化应激的结果，如果氧化应激得到预防，可以改善神经退行性疾病的衰退。这项工作研究了 Klotho 启动子和 3'UTR 随年龄的调节以及氧化损伤随年龄对 Klotho 启动子的影响。我们将确定 Klotho 启动子的高 GC 含量是否使其成为与年龄相关的下调的目标，因为氧化应激会随着时间的推移而积累损伤。这将通过在体外和老年恒河猴大脑的死后样本中比较 Klotho 启动子的氧化态与其他基因的氧化态来完成。我们还将致力于表征结合 Klotho 启动子并诱导其激活的转录因子。 Klotho 启动子不包含转录起始的经典元件。了解哪些因素对 Klotho 转录很重要，可能有助于了解导致 Klotho 激活的信号通路以及 Klotho 在正常细胞中的作用。最后，我们将确定 Klotho 是否受到 microRNA (miR) 的调节，以及 miR 在大脑中如何随着年龄的增长而变化。 MiR 结合并调节 mRNA 的翻译，但关于 miR 是否以及如何影响 Klotho 加工，我们一无所知。同样，了解调节 Klotho 的过程将使我们能够更好地了解影响 Klotho 的过程以及 Klotho 在细胞功能中的更广泛作用。这项工作的结果将增加关于抗衰老基因 Klotho 的新知识，并阐明氧化损伤如何选择性下调特定基因的可能机制。公共卫生相关性：随着人口迅速老龄化，预计未来 50 年与年龄相关的疾病的增加将达到前所未有的水平。了解已知影响衰老过程和受衰老过程影响的基因的调控对于开发针对一系列疾病的新疗法至关重要。衰老抑制蛋白 Klotho 在大脑中随着年龄的增长而减少，可能是神经退行性疾病治疗开发的目标。