Amelioration of aged endothelial dysfunction by NAMPT and caloric restriction

描述(申请人提供)：候选人。候选人安东尼·J·多纳托博士是犹他大学内科系的心血管生理学家。多纳托博士的研究重点是动脉老化的调节机制，以及热量限制可以在衰老过程中保护和恢复血管健康的机制。他的长期目标是领导一个独立的、由外部资助的研究实验室，能够在基因、细胞、组织和全身(全身)水平上综合研究血管衰老，并被公认为翻译血管功能的国际领先者。拟议的K02奖项将为多纳托博士提供必要的职业发展保障时间，以实现这一目标。职业发展计划。这一奖项将支持多纳托博士进一步的职业发展，使他能够在继续接受老年医学培训的同时，完成分子遗传学和衰老基础生物学方面的全面课程。职业发展计划包含几个单独但协调的努力，以提高申请人的专业知识，包括与内皮激活和可诱导转基因小鼠创造相关的新实验技术培训，旨在促进高级学位研究人员更好地理解分子遗传学应用的教学课程工作，以及继续参加定期举行的老龄化和老年医学研讨会系列会议以及其他旨在教育和鼓励多纳托博士和其他研究人员在老龄生物学和老年研究专业领域进行合作研究的会议。研究。本研究的目的有两个方面：一是确定SIRT-1对内皮细胞随年龄增长激活的调节作用以及长期热量限制所诱导的血管保护作用；二是确定基因上调内皮细胞NAMPT表达/活性是否可以改善与年龄相关的内皮功能障碍。这些新颖而重要的研究将确定NAMPT是否以及如何影响sirtuins和随后的炎症/氧化应激相关的血管老化。预期的结果将为临床提供 关于全球内皮功能障碍随年龄增长而表达的综合生理机制以及NAMPT是否为潜在的治疗靶点的重要信息。

DESCRIPTION (provided by applicant): Candidate. The candidate, Anthony J. Donato Ph.D., is a cardiovascular physiologist in the Department of Internal Medicine at the University of Utah. Dr. Donato's research focuses on the mechanisms mediating arterial aging and the mechanisms by which caloric restriction can preserve and restore vascular health with aging. His long term goal is to direct an independent, extramurally-funded research laboratory that can integratively study vascular aging at the gene, cellular, tissue and systemic (whole-body) levels and to be recognized as an international leader in translational vascular function. The proposed K02 award will provide Dr. Donato the necessary protected career development time to achieve this goal. Career Development Plan. This award will support the further career development of Dr. Donato, allowing him to complete a well-rounded program in molecular genetics and the basic biology of aging while maintaining his training in Geriatrics. The career development plan contains several separate but coordinated efforts to enhance the expertise of the applicant including training in new experimental techniques related to endothelial activation and inducible transgenic mouse creation, didactic course work designed to facilitate better understanding of the application of molecular genetics for investigators with advanced degrees and continued attendance at regular aging and geriatric seminar series and other vascular and basic biology of aging meetings aimed to educate and encourage collaborative research between Dr. Donato and other investigators in the specialties of biology of aging and geriatric research. Research. The aim of the research project is twofold: first, determine the modulatory influence of SIRT-1 on endothelial activation with aging and the vasoprotection induced by long term caloric restriction; second, to determine if genetically augmenting endothelial NAMPT expression/activity can ameliorate age-related endothelial dysfunction. These novel and important studies will determine if, and how, NAMPT influences sirtuins and subsequent inflammation/oxidative stress- related vascular aging. The expected results will provide clinically important information regarding the integrative physiological mechanisms by which global endothelial dysfunction is expressed with aging and if NAMPT is a potential therapeutic target.