Amelioration of aged endothelial dysfunction by NAMPT and caloric restriction

描述（由申请人提供）：候选人。候选人Anthony J. Donato博士是犹他大学内科的心血管生理学家。Donato博士的研究重点是动脉老化的机制，以及热量限制可以保护和恢复衰老血管健康的机制。他的长期目标是领导一个独立的，校外资助的研究实验室，可以在基因，细胞，组织和系统（全身）水平上综合研究血管衰老，并在转化血管功能方面被公认为国际领先。拟议的K02奖将为Donato博士提供必要的受保护的职业发展时间，以实现这一目标。职业发展计划。该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病学培训的同时，完成分子遗传学和衰老基础生物学的全面课程。职业发展计划包括几项独立但协调的努力，以提高申请人的专业知识，包括内皮细胞激活和诱导转基因小鼠创造相关的新实验技术的培训；教学课程的目的是为了更好地理解分子遗传学的应用，为拥有高级学位的研究人员提供帮助，并继续参加定期的衰老和老年医学研讨会系列以及其他血管和老年医学基础生物学会议，旨在教育和鼓励Donato博士与其他研究人员在衰老和老年医学生物学专业方面的合作研究。研究。该研究项目的目的是双重的：首先，确定SIRT-1对随着年龄增长的内皮细胞激活和长期热量限制诱导的血管保护的调节作用；其次，确定基因增强内皮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衰老。预期结果将提供临床

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.