BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10618254
• 负责人: ARLAN G. RICHARDSON
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10618254
• 关键词: Acceleration; Affect; Age; Age Years; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Anesthesia procedures; Animals; Antioxidants; Applications Grants; Area; Atherosclerosis; Attenuated; Award; Biological Assay; Caring; Carrageenan; Cell Aging; Cell Death; Cell Death Induction; Cells; Chronic; Cities; Cognition; Communities; Cytolysis; DNA Methylation; Data; Diabetes Mellitus; Diet; Disease; Elderly; Epigenetic Process; Epithelial Cells; Exercise; Faculty; Female; Foundations; Funding; Future; Gene Expression; Genes; Genetic Transcription; Genome; Genotype; Geroscience; Glutathione; Goals; Grant; Health; Health Sciences; Human; Inbreeding; Inflammation; Institution; Intervention; Intestinal Mucosa; Intestines; Invertebrates; Knockout Mice; Laboratories; Lead; Longevity; Malignant Neoplasms; Manuscripts; Measures; Medical Research; Medical center; Memory; Molecular; Mouse Strains; Mus; Necrosis Induction; Neurofibrillary Tangles; Observational Study; Oklahoma; Organism; Oxidation-Reduction; Oxidative Stress; Paper; Parkinson Disease; Pathology; Pathway interactions; Pattern; Play; Postdoctoral Fellow; Preparation; Primates; Publishing; Recombinants; Recovery; Reporting; Research; Research Personnel; Research Project Grants; Resolution; Risk Factors; Rodent; Role; Scientist; Seminal; Shock; Sirolimus; Site; Superoxide Dismutase; System; Testing; Tissues; Transgenic Mice; Transgenic Organisms; United States Department of Veterans Affairs; United States National Institutes of Health; Universities; Veterans; age effect; age related; anti aging; base; career; catalase; cost; demographics; dietary restriction; feeding; frailty; genetic manipulation; graduate student; healthspan; improved; in vivo; interest; male; military veteran; mouse model; novel; overexpression; oxidative damage; pharmacologic; prevent; promoter; resilience; response; stem cells; superoxide dismutase 1; treadmill

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.

项目摘要/摘要：理查森博士研究的总体目标是确定 导致衰老的分子途径，旨在产生延缓衰老、延缓/预防的疗法 防治与年龄相关的疾病，提高老年人的健康水平。他的 VA 研究重点是氧化作用 压力和损害在衰老过程中的作用使他最近获得了退伍军人管理局优异奖，该基金研究了衰老过程中压力和损伤的作用 衰老过程中的炎症。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 与年龄相关的疾病，例如癌症、健康疾病、阿尔茨海默病等。坏死性凋亡是最近发现的一种 程序性坏死途径，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，是炎症的有效诱导物。利用遗传 理查森博士将确定减少小鼠坏死性凋亡是否会减弱 与年龄相关的慢性炎症增加，从而延长寿命、改善健康状况， 减少小鼠与年龄相关的病理。 理查森博士还是三项 NIH 资助项目的 PI。他的第一个 NIH 拨款研究饮食限制（DR）， 已被证明可以延长从无脊椎动物到啮齿动物等多种生物体的寿命。 因此，DR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对 DR 作出反应的能力的主要决定因素，例如，三分之二的 研究中的 41 只重组近交 (RI) 系小鼠要么没有反应，要么表现出寿命缩短 美联储博士。他获得 NIH 资助的总体目标是探索基因型与 DR 水平之间的相互作用 据报道，使用 4 只 RI 品系的小鼠，当喂食 DR 饮食时，它们的寿命会缩短。寿命和 在随意喂养或 60% ad 喂养的雄性和雌性小鼠中测量与衰老相关的病理学 自由采食（DR）。目前的数据表明，与之前的报告相比，DR 延长了 小鼠 RI 系，支持 DR 是一种普遍的衰老干预措施的观点。 理查森博士的第二笔 NIH 拨款是为了响应 RFA，以开发小鼠的恢复能力测量方法， 可以作为延长寿命和健康寿命的替代品。他正在制定四种复原力衡量标准： 相对简单、廉价、非侵入性，并且可以在小鼠体内进行。目前，他的实验室是 研究年龄、DR 和雷帕霉素对以下恢复能力的反应：跑步机锻炼、从 麻醉、角叉菜胶诱导的炎症以及氧化应激的恢复。 在最近资助的第三项 NIH 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，他表明短期 DR 会诱导 DNA 甲基化的变化 Nts 1 基因启动子中的肠粘膜。 DNA甲基化的变化密切相关 随着 Nts 1 表达的增加，当 DR 小鼠随意喂食数次后，这种情况持续存在。 几个月。由于肠粘膜上皮细胞每4～5天不断更新一次， 肠粘膜 DNA 甲基化的变化最有可能发生在肠干细胞中。在这笔资助中，博士。 Richardson 正在使用一种新型方法测量肠道干细胞中 DR 诱导的 DNA 甲基化变化 测定，这使他能够以单碱基分辨率准确测量约 30 的 DNA 甲基化变化 基因组中的百万个位点。 除了研究资助之外，理查森博士还是 P30 NIA 中心资助项目的 PI/主任： 俄克拉荷马州内森休克老化中心。俄克拉荷马州休克中心包括来自三个专业的教员 俄克拉荷马城研究机构：俄克拉荷马大学健康科学中心、俄克拉荷马医学院 研究基金会和 OKC VA 医疗中心。该中心提供教师、博士后、 以及三个机构的研究生，他们采用独特的方法来研究老龄化和试点补助金。