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，目的是产生延迟衰老的疗法，延迟/预防 与年龄相关的疾病，并改善较早的健康状况。他的VA研究集中于氧化物的角色 衰老中的压力和伤害发挥，这导致了他最近资助的VA优异赠款 衰老中的炎症。慢性低级炎症是衰老的标志，是大多数人的主要危险因素 与年龄有关的疾病，例如癌症，健康疾病，阿尔茨海默氏病等。坏死性是最近发现的 通过细胞裂解诱导细胞死亡的程序性坏死的途径，导致释放 损伤相关的分子模式，它们是炎症的潜在诱导剂。使用遗传 减少小鼠坏死性的操纵，理查森博士将确定减少坏死病减弱 慢性感染与年龄有关的增加，并导致寿命增加，改善了健康范围，以及 小鼠年龄相关的病理减少。 理查森博士也是三项NIH赠款的PI。他的第一个NIH赠款研究饮食限制（DR）， 我们被证明会增加从无脊椎动物到啮齿动物的各种生物的寿命。 因此，DR被视为普遍的衰老干预措施。但是，2010年的一项研究报告说 动物的基因型是动物对DR作出反应的能力的主要决定者，例如三分之二的动物。 研究的小鼠的41个重组近交（RI）系在 美联社他的NIH赠款的总体目标是探索基因型与博士水平之间的相互作用 据报道，使用四只小鼠的RI系列在喂养DR饮食时显示出寿命的降低。寿命和 在喂养的雄性和雌性小鼠中，与衰老相关的病理正在喂养或60％的AD 雌性（DR）。当前的数据表明，与先前的报告相反，DR提高了 小鼠的RI线，支持DR是普遍衰老干预的观点。 理查森博士的第二次NIH赠款是对RFA的回应，以开发老鼠的弹性测量值 可以代替代寿命和健康状态。他正在制定四种弹性措施 相关的简单，廉价，无创的，可以在体内小鼠中进行。目前，他的实验室是 研究年龄，DR和雷帕霉素对以下弹性的反应：跑步机运动，从 麻醉，角叉菜胶引起的感染以及从氧化应激中恢复。 理查森博士在最近资助的第三名NIH赠款中研究了表观遗传学在 DR的抗衰老机制。最近，他表明短期DR诱导了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的表达增加，当Dr小鼠随后将DR小鼠喂食时持续存在。 月份。由于肠粘膜中的上皮细胞每4至5天连续更新一次 肠粘膜中DNA甲基化的变化很可能是肠道干细胞中发生的。在这笔赠款中，博士 理查森正在测量使用一种新颖的肠道干细胞中DR诱导的DNA甲基化的变化 测定，这使他能够在单碱基分辨率下准确测量〜30时DNA甲基化的变化 基因组中的百万个地点。 除了他的研究赠款外，理查森博士还是PI/P30 NIA中心赠款的PI/主任： 俄克拉荷马州内森冲击老化中心。俄克拉荷马州冲击中心涉及三个专业的教师 俄克拉荷马城的研究机构：俄克拉荷马大学健康科学中心，俄克拉荷马州医疗 研究基金会和OKC VA医疗中心。该中心的戏剧提供教师，博士后研究员， 以及三个机构的研究生，他们有独特的测定法，以研究老化和飞行员补助。