Klotho Regulation and Aging

Klotho 调节和衰老

基本信息

批准号：
8293044
负责人：
Gwendalyn DiAnn King
金额：
$ 24.23万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8293044
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 abstracting 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 response therapeutic development transcription factor

项目摘要

Project Abstract 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.

项目摘要我们研究的重点是研究年龄抑制蛋白 Klotho 是如何随着衰老而受到调节的在大脑中。当 Klotho 表达被消除时，小鼠发育正常，但衰老至死亡时间为 4 岁月龄。这种快速恶化伴随着与观察到的不同的表型老年人（认知障碍、动脉粥样硬化、异位钙化、肺气肿、骨质疏松症、皮肤萎缩和脱发、胸腺退化、不孕和骨矿物质减少密度）。消除小鼠中的 Klotho 会导致认知障碍，这与增加氧化应激。相比之下，Klotho 过度表达的转基因小鼠寿命延长了 30%，并且抵抗氧化应激。我们的小组发现 Klotho 在衰老的非人类动物中表达下调灵长类动物、大鼠和小鼠的大脑共同使我们推测 Klotho 很重要大脑功能的变化及其随着年龄的增长而下调可能是氧化应激的结果，如果预防，可以改善神经退行性疾病的衰退。提出的工作，审查 Klotho启动子和3'UTR随年龄的调节以及氧化损伤对 Klotho启动子随着年龄的增长。我们将确定Klotho启动子是否具有高GC含量由于损害随着时间的推移而累积，使其成为与年龄相关的下调目标因为氧化应激。这将通过比较 Klotho 的氧化态来完成体外和老年恒河猴死后样本中其他基因的启动子脑。我们还将致力于表征结合并诱导激活的转录因子克洛托发起人。 Klotho 启动子不包含经典的转录元件引发。了解哪些因素对 Klotho 转录很重要可能有助于阐明导致 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 microRNA (miR) 调节以及 miR 在大脑中如何变化年龄。 MiR 结合并调节 mRNA 的翻译，但对于 miR 是否以及如何结合尚不清楚影响 Klotho 处理。再次强调，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 在细胞中的更广泛作用功能。这项工作的结果将为抗衰老基因 Klotho 和阐明氧化损伤如何选择性下调特定基因的可能机制。