Mitochondrial Protection to Derive Expanded Aged Renal Glomerular Progenitor Cells

摘要：线粒体对扩增的老年肾小球祖细胞的保护作用 应聘者：此K01职业发展奖申请表描述了以下项目的研究和培训活动 Mariya T.Sweetwyne博士，华盛顿大学病理学系肾细胞生物学家 华盛顿，西雅图。她的直接职业目标是将她在肾脏生物学方面的既定训练与 新获得的和正在进行的细胞衰老生物学方面的培训。从长远来看，她打算建立一个 独立研究计划专注于开发干预措施来改善细胞衰老的影响 治疗慢性和急性肾小球疾病。在这份申请中，Sweetwyne博士提出了具体的 目的探讨线粒体功能障碍在衰老肾小球上皮细胞病理中的作用。 研究：肾脏衰老的标志是肾小球滤过单位的纤维化改变，这会导致 随着年龄的增长，患慢性肾脏疾病的风险增加。Sweetwyne博士之前的研究 等人的研究。证明用四肽伊拉米肽(SS-31/Bendavia)治疗老年小鼠，以保存 线粒体内膜结构显著减少了肾老化对肾小球的损害，提示 老年人肾脏可塑性的关键之一在于线粒体的健康。该提案建立在这些调查结果的基础上，以 问：(目标1)在特定的肾小球上皮细胞中，线粒体功能的哪个方面得到改善？(目标2) 线粒体的改善如何导致观察到的肾小球细胞衰老的减少，(目标3)和 这些已知的增强是否会影响衰老和衰竭的肾脏的再生潜力 小鼠和人的祖细胞。职业发展计划：这项建议符合斯威特因博士的观点 通过在三个关键领域培养她在衰老生物学方面的专业知识，实现长期目标：(1) 线粒体能量学评价，(2)蛋白质组学的应用，(3)原代细胞的分离和培养 人尿来源的祖细胞。专业学术发展活动包括：正式毕业 在衰老生物学方面的课程工作，在国家科学会议上发表研究报告，并定期 安排了与职业导师的会议。环境：Sweetwyne博士在大学接受培训的环境 华盛顿大学(UW)是个例外。她的多学科指导团队由资深学生组成 精通线粒体能量学、衰老生物学或肾脏病的教职员工。斯威特温博士的校长 导师拉比诺维奇博士被公认为老龄化领域的领导者，并成功地指导了多个 学员通过K01和K99/R00奖项。UW Radiology的共同导师David Marcinek博士是 衰老或损伤肌肉中的线粒体能量学和氧化应激。共同导师Behzad Najafian博士 威斯康星大学病理学系临床肾脏病理学家，是培养人肾小球的专家 从活检和尿液中分离出的上皮细胞。所有导师都与Dr. 因此，他们致力于实现本文所述的科学和专业目标。

Abstract: Mitochondrial Protection to Derive Expanded Aged Renal Glomerular Progenitor Cells Candidate: This K01 career development award application describes research and training activities for Mariya T. Sweetwyne, Ph.D. a renal cell biologist in the department of Pathology at the University of Washington, Seattle. Her immediate career goal is to combine her established training in renal biology with newly acquired and on-going training in the biology of cellular aging. Long-term, she intends to build an independent research program focused on developing interventions to ameliorate the impact of cellular aging on both chronic and acute renal glomerular diseases. In this application, Dr. Sweetwyne proposes specific aims to determine the role of mitochondrial dysfunction on the pathologies of aging glomerular epithelial cells. Research: Aging in the kidney is marked by fibrotic changes to the glomerular filtration units, which lead to increased risk of developing chronic kidney disease with advancing age. Previous studies from Dr. Sweetwyne et al. demonstrated that treating old mice with a tetrapeptide, Elamipretide (SS-31/Bendavia), to preserve mitochondrial inner membrane structure significantly reduced glomerular damage from renal aging, suggesting that one key to renal plasticity in the aged lies in mitochondrial health. This proposal builds on those findings to ask: (Aim 1) which aspect of mitochondrial function is improved in specific glomerular epithelial cells, (Aim 2) how mitochondrial improvement results in observed reduction of glomerular cell senescence, (Aim 3) and whether these known enhancements will affect the regenerative potential of aged and depleted renal progenitor cells in mouse and man. Career Development Plan: This proposal serves Dr. Sweetwyne’s short and long-term goals by building her bench expertise in the biology of aging in three critical areas: (1) assessment of mitochondrial energetics, (2) utilization of proteomics, and (3) isolation and culture of primary human urine-derived progenitor cells. Professional academic development activities include: formal graduate course work in the biology of aging, presentation of research at national scientific conferences and routinely scheduled meetings with career mentors. Environment: The environment for Dr. Sweetwyne’s training at the University of Washington (UW) is exceptional. Her multidisciplinary mentoring team is comprised of senior faculty who are experts in mitochondrial energetics, aging biology, or nephrology. Dr. Sweetwyne’s principal mentor, Dr. Rabinovitch, is recognized as a leader in the field of aging and has successfully mentored multiple trainees through K01 and K99/R00 awards. Co-mentor Dr. David Marcinek of UW Radiology is an expert in mitochondrial energetics and oxidative stress in aging or injured muscle. Co-mentor Dr. Behzad Najafian of UW Pathology is a board certified Clinical Renal Pathologist and is expert in culture of human renal glomerular epithelium isolated from biopsies and urine. All mentors have established professional collaborations with Dr. Sweetwyne and are thus invested in the success of the scientific and professional aims outlined herein.