Metformin to improve immunological health and vaccine responses

二甲双胍改善免疫健康和疫苗反应

• 批准号: 10356874
• 负责人: Grace Choi Lee
• 金额: $ 15.94万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10356874
• 关键词: Address; Adjuvant; Adult; Age; Age-Years; Aging; Antibody Response; Area; Award; Biometry; Capsicum; Cessation of life; Clinical; Clinical Research; Clinical Trials; Data; Deterioration; Diabetes Mellitus; Disease; Double-Blind Method; Drug usage; Educational Activities; Elderly; Environment; Epidemiology; Evaluation; Experimental Models; Foundations; Funding; Future; Gene Expression; Genomics; Goals; Health; Health Promotion; Immune; Immune system; Immunogenetics; Immunoglobulin G; Immunoglobulin M; Immunologic Markers; Immunologics; Immunology; Impairment; Infection; Institutes; Interleukin-6; Intervention; Investigation; K-Series Research Career Programs; Lead; Link; Longevity; Mediating; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Metformin; Modeling; Molecular; Monitor; Mus; Operative Surgical Procedures; Participant; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacists; Pharmacology; Placebos; Plasma; Pneumococcal Infections; Pneumococcal conjugate vaccine; Pneumococcal vaccine; Population; Predisposition; Primary Prevention; Process; Program Development; Randomized; Research; Research Activity; Research Personnel; Resources; Role; Scientist; Sirolimus; Streptococcus pneumoniae; Stress; Supervision; TNF gene; Testing; Therapeutic; Training; Vaccination; Vaccines; base; biological adaptation to stress; career development; cohort; combinatorial; comorbidity; design; experience; feasibility testing; genomic signature; healthspan; healthy aging; hospitalization rates; immune function; immune health; immunoregulation; immunosenescence; improved; inflammatory marker; influenza virus vaccine; innovation; mortality; novel; pilot trial; preservation; primary outcome; programs; prospective; public health relevance; randomized placebo-controlled clinical trial; resilience; response; secondary outcome; skills; transcriptome sequencing; trend; universal vaccine; vaccine effectiveness; vaccine response

Abstract This Mentored Patient-Oriented Research Career Development Award (K23) seeks to equip Dr. Grace Lee with the skill requisites needed to develop into a leading translational geroscientist focused on evaluating pharmacological interventions to improve immunological health. The career development program outlines supervised research and educational activities to achieve the following training objectives: (1) gain skills in integrating clinical and molecular approaches in prospective clinical trials of aging; (2) interpret and apply immunogenetic data to characterize immune resilience in aging; and (3) gain skills needed to transition to independent funding. Deterioration of immune function is a hallmark of most age-associated diseases. Thus, identifying therapeutically modifiable pathways that underpin the aging-associated immune decline are needed to improve health span/lifespan. The overall objective of this study is to test a widely used diabetes drug, metformin, to improve immunological integrity as a marker of resilience. This K23 application builds on preliminary data acquired while as a RL5 Pepper Center Scholar, which (i) identified that metformin was associated with improved pneumococcal conjugate vaccine (PCV13) responses in mice, and (ii) established feasibility of a clinical trial using metformin to improve immunological resilience in older adults. Additionally, through evaluation of a ~70,000 person cohort, working with my mentor, we have identified genomic and immunologic correlates of an immunosenescence-mediating program that contributes to age-associated decline in immunological integrity, including vaccine responses and mortality. For this K23, we propose to conduct a pilot double-blind randomized placebo-controlled clinical trial of adults 50 to 65 years of age. Eligible subjects will be randomized in a 1:1 ratio to metformin (titrated to 2,000 mg/day) or placebo for a total duration of 5 months. After completing a 16 week course of study drug, subjects will be administered the PCV13, then followed for an additional 4 weeks on treatment. We will compare PCV13 vaccine responsiveness and improvements in novel genomic signatures associated immunological integrity in adults treated with metformin compared to placebo. The findings from this study will provide the necessary pilot data for future, more definitive studies that will advance our understanding of metformin’s role on the aging immune system. This proposal is supported by a mentorship team of renowned scientists in immunology/genomics (Dr. Ahuja), aging research (Drs. Musi and Espinoza), and pneumococcal diseases (Dr. Restrepo), and an advisor in biostatistics (Dr. Gelfond). This team, along with resources available through the San Antonio Pepper Center and Barshop Institute for Longevity and Aging Studies, comprise an ideal environment for Dr. Lee to successfully reach her goal to promote healthy aging.

抽象的 这项受到指导的以患者为导向的研究职业发展奖（K23）旨在为Grace Lee博士配备 该技能需要发展为主要的转化式geroscientist，专注于评估 改善免疫健康的药理干预措施。职业发展计划概述 监督研究和教育活动以实现以下培训目标：（1）获得技能 在衰老的前瞻性临床试验中整合临床和分子方法； （2）解释并应用 免疫遗传数据以表征衰老中的免疫力； （3）过渡到所需的技能 独立资金。免疫学功能的恶化是大多数年龄相关疾病的标志。那， 需要确定需要修改的可修改途径，这些途径需要支撑与衰老相关的免疫下降 改善健康跨度/寿命。这项研究的总体目的是测试广泛使用的糖尿病药物， 二甲双胍，以提高免疫学完整性作为弹性的标志。此K23应用程序建立在 作为RL5胡椒中心学者而获得的初步数据，（i）确定二甲双胍是 与改善小鼠肺炎球菌结合疫苗（PCV13）反应有关，（ii）已建立 使用二甲双胍临床试验的可行性来改善老年人的免疫弹性。此外， 通过评估约70,000人的队列，与我的心理合作，我们已经确定了基因组和 免疫中断计划的免疫学相关性，该计划有助于与年龄相关 免疫完整性的下降，包括疫苗反应和死亡率。对于此K23，我们建议 进行50至65岁的成年人的双盲随机安慰剂对照临床试验。有资格的 受试者将以1：1的比例与二甲双胍（滴定至2,000 mg/天）或安慰剂的总持续时间进行随机分配 5个月。完成为期16周的学习药物后，将对受试者进行PCV13的管理，然后 随后再进行4周的治疗。我们将比较PCV13疫苗响应能力和 用二甲双胍治疗的成年人的免疫完整性的新型基因组特征的改善 与安慰剂相比。这项研究的发现将为未来提供必要的试点数据，更多 确定的研究将提高我们对二甲双胍在衰老免疫系统中的作用的理解。这 提案得到了一个著名的免疫学/基因组科学科学家（Ahuja博士）的心态团队，衰老 研究（Musi和Espinoza博士）和肺炎球菌疾病（Restrepo博士），以及生物统计学的顾问 （Gelfond博士）。该团队以及通过圣安东尼奥胡椒中心和酒吧提供的资源 长寿与老化研究所，为李博士成功与她联系的理想环境 促进健康衰老的目标。