BLR&D Research Career Scientist Award Application

项目概要/摘要：Richardson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、延迟/预防 与年龄有关的疾病，改善老年人的健康。他的退伍军人管理局研究集中在氧化的作用 压力和损伤在衰老中的作用，这导致了他最近资助的VA Merit赠款，该赠款研究了 炎症在老化。慢性低度炎症是衰老的标志，也是大多数人的主要危险因素。 与年龄有关的疾病，例如，癌症、健康疾病、阿尔茨海默病等。坏死性下垂是最近发现的一种 程序性坏死途径，通过细胞溶解诱导细胞死亡，导致释放 损伤相关的分子模式，这是炎症的有效诱导剂。使用遗传学 减少小鼠坏死性凋亡的操作，理查森博士将确定减少坏死性凋亡是否会减弱 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， 减少小鼠中与年龄相关的病理学。 Richardson博士也是三个NIH赠款的PI。他的第一个NIH资助研究饮食限制（DR）， 已被证明可以增加从无脊椎动物到啮齿动物的各种生物的寿命。 因此，DR已被视为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响应DR的能力的主要决定因素，例如，三分之二的 研究的41个重组近交系小鼠， 他的NIH资助的总体目标是探索基因型和DR水平之间的相互作用 使用四种RI系小鼠，据报道，当喂食DR饮食时，显示寿命缩短。寿命和 与衰老相关的病理学在随意喂食或60%AD的雄性和雌性小鼠中进行测量 自由采食（DR）。目前的数据表明，与以前的报告相比，DR延长了 RI系小鼠，支持DR是一种普遍的衰老干预措施的观点。 Richardson博士的第二个NIH基金是对RFA的回应，用于开发小鼠恢复力的测量方法， 可以作为延长寿命和健康寿命的替代品。他正在开发四种衡量韧性的方法， 相对简单、便宜、非侵入性，并且可以在小鼠体内进行。目前，他的实验室 研究年龄，DR和雷帕霉素对以下恢复力的反应：跑步机运动， 麻醉、角叉菜胶诱导的炎症和从氧化应激中恢复。 在最近获得的第三笔NIH资助中，Richardson博士正在研究表观遗传学在遗传学中的潜在作用。 最近，他发现短期DR诱导DNA甲基化的变化， 肠粘膜中的Nts 1基因的启动子。DNA甲基化的改变与细胞凋亡密切相关， 随着Nts 1表达的增加，当DR小鼠被随意喂养数周后， 个月由于肠粘膜上皮细胞每4 ~ 5天不断更新， 肠粘膜中DNA甲基化的变化最可能发生在肠干细胞中。在这一点上，博士。 Richardson正在使用一种新的方法来测量肠道干细胞中DR诱导的DNA甲基化的变化。 这使他能够在单碱基分辨率下准确测量DNA甲基化在~30 基因组中的百万个位点。 除了他的研究赠款，理查森博士也是PI/主任的P30 NIA中心补助金： 俄克拉荷马州内森休克老化中心。俄克拉荷马州休克中心涉及来自三个主要的教师 俄克拉荷马州市的研究机构：俄克拉荷马州大学健康科学中心，俄克拉荷马州医学 研究基金会和OKC VA医疗中心。该中心提供教师，博士后研究员， 和研究生在这三个机构与独特的分析研究老化和试点赠款。

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.