BLR&D Research Career Scientist Award Application

项目摘要/摘要：理查森博士研究的首要目标是确定 导致衰老的分子途径，目的是产生延缓衰老、延缓/预防衰老的疗法 与年龄相关的疾病，并改善老年人的健康。他的退伍军人事务部研究重点放在氧化的作用上 压力和损伤在衰老中发挥了作用，这导致了他最近获得的退伍军人奖励基金，该基金研究了 衰老过程中的炎症。慢性低度炎症是衰老的标志，是大多数人的主要危险因素 与年龄有关的疾病，如癌症、健康疾病、阿尔茨海默病等。 程序性坏死的一种途径，通过细胞裂解诱导细胞死亡，导致释放 损伤相关的分子模式，这是炎症的有力诱因。使用遗传性 减少小鼠坏死性下垂的手法，理查森博士将确定减少坏死性下垂是否会减弱 与年龄相关的慢性炎症增加并导致寿命延长，健康状况改善，以及 减少小鼠年龄相关的病理改变。 理查森博士也是美国国立卫生研究院三项拨款的私人侦探。他的第一笔NIH拨款研究饮食限制(DR)，这项研究 已被证明可以延长从无脊椎动物到啮齿类动物的各种生物的寿命。 因此，DR被认为是一种普遍的衰老干预措施。然而，2010年的一项研究报告称， 动物的基因型是动物对DR做出反应的能力的主要决定因素，例如三分之二 所研究的41个重组近交系小鼠要么没有反应，要么表现出寿命缩短 他的NIH拨款的总体目标是探索基因和DR水平之间的相互作用。 据报道，使用四个RI系的小鼠，当喂食DR饮食时，寿命会减少。它的寿命和 与衰老相关的病理在随意喂养或60%AD的雄性和雌性小鼠中进行测量 锂(DR)。目前的数据表明，与前一份报告相反，DR延长了 RI系小鼠，支持DR是一种普遍的衰老干预的观点。 理查森博士的第二笔NIH赠款是对RFA的回应，RFA旨在开发小鼠的弹性测量 可以作为替代品，延长寿命和健康寿命。他正在制定四项衡量韧性的措施，这四项措施是 相对简单，价格低廉，无创，可以在小鼠体内进行。目前，他的实验室是 研究年龄、DR和雷帕霉素对以下各项的恢复能力的反应：跑步机运动，恢复 麻醉，角叉菜胶引起的炎症，以及从氧化应激中恢复。 在最近由美国国立卫生研究院资助的第三笔拨款中，理查森博士正在研究表观遗传学在 DR的抗衰老机制最近，他发现短期DR可引起脑内DNA甲基化的改变 肠粘膜中NTS-1基因的启动子。DNA甲基化的变化密切相关 随着NTS-1表达的增加，当DR小鼠被随意喂养几个小时后，这种表达持续存在 月份。由于肠粘膜中的上皮细胞每4至5天持续更新一次，因此 肠粘膜DNA甲基化的变化很可能发生在肠道干细胞中。在这笔赠款中，Dr。 理查森正在使用一种新的方法测量DR诱导的肠道干细胞DNA甲基化的变化 分析，这使他能够在单碱基分辨率下准确地测量DNA甲基化在~30 基因组中有一百万个位点。 除了他的研究资助外，理查森博士也是P30 NIA中心拨款的PI/主任： 俄克拉荷马州内森休克老龄中心。俄克拉荷马州休克中心有来自三大 俄克拉荷马城研究机构：俄克拉荷马大学健康科学中心，俄克拉荷马医学 研究基金会和俄克拉何马州退伍军人医学中心。该中心提供教师、博士后研究员、 以及这三个机构的研究生，他们用独特的方法研究老龄化和试点助学金。

Project Summary/Abstract: The overarching goal of Dr. Richardson’s research has been to identify the molecular pathways that lead to aging with the purpose of generating therapies that retard aging, delay/prevent age-related diseases, and improve the health of the elderly. His VA research has focused on the role oxidative stress and damage play in aging that has led to his recently funded VA Merit grant, which studies the role of inflammation in aging. Chronic, low-grade inflammation is a hallmark of aging and is a major risk factor for most age-related diseases, e.g., cancer, health disease, Alzheimer’s disease, etc. Necroptosis is a recently identified pathway of programmed necrosis that induces cell death through the lysis of cells, resulting in the release of damage-associated molecular patterns, which are potent inducers of inflammation. Using genetical manipulations that reduce necroptosis in mice, Dr. Richardson will determine if reducing necroptosis attenuates the age-related increase in chronic inflammation and leads to increased lifespan, improved healthspan, and reduced age-related pathology in the mice. Dr. Richardson also is PI on three NIH grants. His first NIH grant studies dietary Restriction (DR), which has been shown to increase the lifespan of a wide variety of organisms ranging from invertebrates to rodents. Therefore, DR has been viewed as a universal aging intervention. However, a study in 2010 reported that the genotype of an animal was a major determinant in the ability of the animal to respond to DR, e.g., two-thirds of the 41 recombinant inbred (RI) lines of mice studied either did not respond or showed reduced lifespan when fed DR. The overall goal of his NIH grant is to explore the interaction between genotype and the level of DR using four of the RI lines of mice reported to show a decrease in lifespan when fed a DR diet. The lifespan and pathology associated with aging is being measured in male and female mice fed either ad libitum or 60% ad libitum (DR). The current data indicate that in contrast to the previous report, DR increases the lifespan of the RI lines of mice, supporting the view that DR is a universal aging intervention. Dr. Richardson’s second NIH grant is in response to an RFA to develop measures of resilience in mice that can be surrogates for increased longevity and healthspan. He is developing four measures of resilience that are relatively simple, inexpensive, non-invasive, and can be performed in mice in vivo. Currently, his laboratory is studying the response of age, DR, and rapamycin on resilience to the following: treadmill exercise, recovery from anesthesia, carrageenan-induced inflammation, and recovery from oxidative stress. In a recently funded third NIH grant, Dr. Richardson is studying the potential role epigenetics plays in the anti-aging mechanism of DR. Recently, he showed that short-term DR induces changes in DNA methylation in intestinal mucosa in the promoter of the Nts 1 gene. The changes in DNA methylation were closely associated with increased expression of Nts 1, which persisted when the DR mice were then fed ad libitum for several months. Because the epithelial cells in the intestinal mucosa are continuously renewed every 4 to 5 days, the changes in DNA methylation in intestinal mucosa most likely arise in intestinal stem cells. In this grant, Dr. Richardson is measuring changes in DNA methylation induced by DR in intestinal stem cells using a novel assay, which allows him to measure accurately at single base resolution changes DNA methylation at ~30 million sites in the genome. In addition to his research grants, Dr. Richardson is also the PI/Director of a P30 NIA Center grant: the Oklahoma Nathan Shock Aging Center. The Oklahoma Shock Center involves faculty from the three major research institutions in Oklahoma City: University of Oklahoma Health Sciences Center, Oklahoma Medical Research Foundation, and OKC VA Medical Center. The Center plays provides faculty, post-doctoral fellows, and graduate students at the three institutions with unique assays to study aging and pilot grants.