Mitochondrial Protection to Derive Expanded Aged Renal Glomerular Progenitor Cells

线粒体保护以衍生扩大的老化肾小球祖细胞

• 批准号: 10117162
• 负责人: Mariya Ts'ana Sweetwyne
• 金额: $ 12.38万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10117162
• 关键词: Acute; Acute Renal Failure with Renal Papillary Necrosis; Adult; Affect; Age; Aging; Animals; Area; Autologous Stem Cell Transplantation; Award; Binding; Biology; Biology of Aging; Biopsy; Blood capillaries; Cardiolipins; Cell Aging; Cell Count; Cell Culture Techniques; Cell Cycle; Cell Density; Cell Lineage; Cell Proliferation; Cells; Cellular biology; Characteristics; Chronic; Chronic Kidney Failure; Clinical; Clinical Research; Collaborations; Collagen Type IV; Development; Development Plans; Diabetes Mellitus; Doctor of Philosophy; Elderly; Environment; Epithelial; Epithelial Cells; Filtration; Future; Genus Hippocampus; Glomerular capsule structure; Goals; Health; High Fat Diet; Human; Hypertension; In Vitro; Injury; Injury to Kidney; Inner mitochondrial membrane; Intervention; K-Series Research Career Programs; Kidney; Kidney Diseases; Lead; Lesion; Life; Light; Measurement; Mediating; Membrane; Mentors; Mesenchymal; Methods; Mitochondria; Mitotic; Molecular; Morphology; Mus; Muscle; Nephrology; Operative Surgical Procedures; Opportunistic Infections; Outcome Measure; Oxidative Phosphorylation; Oxidative Stress; Parietal; Pathologist; Pathology; Pathway interactions; Phenotype; Phospholipids; Population; Predisposition; Proteomics; Radiology Specialty; Regenerative capacity; Rejuvenation; Renal glomerular disease; Research; Research Activity; Respiration; Risk; Role; Rotenone; Schedule; Structure; Therapeutic; Therapeutic Intervention; Training; Training Activity; Universities; Urine; Washington; Work; age related; aged; beta-Galactosidase; career; career development; cell age; chemotherapy; comorbidity; design; experimental study; fluorescence imaging; functional outcomes; glomerular filtration; glomerulosclerosis; improved; in vivo; injured; kidney cell; man; meetings; mesangial cell; mitochondrial dysfunction; multidisciplinary; podocyte; preservation; progenitor; programs; regeneration potential; renal damage; renal epithelium; resilience; response; senescence; senior faculty; sex; stem cells; success; symposium; tool; treatment arm; urinary; young adult

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.

翻译后摘要：线粒体保护，以获得扩增的老年肾小球祖细胞 候选人：此K 01职业发展奖申请描述了以下人员的研究和培训活动 玛丽亚·T Sweetwyne博士他是纽约大学病理学系的肾细胞生物学家， 华盛顿，西雅图。她近期的职业目标是将她在肾脏生物学方面的既定培训与联合收割机结合起来， 新获得的和正在进行的细胞衰老生物学培训。从长远来看，她打算建立一个 一个独立的研究项目，专注于开发干预措施，以改善细胞老化的影响 慢性和急性肾小球疾病的治疗。在本申请中，Sweetwyne博士提出了具体的 目的是确定线粒体功能障碍在衰老肾小球上皮细胞病理学中的作用。 研究：肾脏衰老的标志是肾小球滤过单位的纤维化变化，这会导致 随着年龄的增长，患慢性肾脏疾病的风险增加。来自Sweetwyne博士的研究 等人证明，用四肽Elamipretide（SS-31/Bendavia）治疗老年小鼠， 线粒体内膜结构显著减少了肾脏衰老引起的肾小球损伤，提示 老年人肾脏可塑性的一个关键在于线粒体的健康。本提案以这些调查结果为基础， 问：（目的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，（目的2） 线粒体改善如何导致观察到的肾小球细胞衰老的减少，（目的3）和 这些已知的增强是否会影响老年和衰竭肾的再生潜力， 职业发展计划：此建议符合Sweetwyne博士的短 通过在三个关键领域建立她在衰老生物学方面的专业知识来实现长期目标：（1） 线粒体能量学的评估，（2）蛋白质组学的利用，和（3）分离和培养原代 人尿源性祖细胞。专业学术发展活动包括：正式研究生 课程工作在生物学的老化，介绍研究在国家科学会议和例行 与职业导师安排的会议。环境：Sweetwyne博士在培训中心的环境 华盛顿大学（UW）是一所非常出色的大学。她的多学科指导团队由高级 教师谁是线粒体能量学，衰老生物学，或肾脏学专家。斯威特温博士的校长 Rabinovitch博士被公认为老龄化领域的领导者，并成功地指导了多个 通过K 01和K99/R 00奖励学员。UW放射学的大卫Marcinek博士是一位专家， 线粒体能量学和氧化应激在老化或受伤的肌肉。共同导师Behzad Najafian博士， UW病理学是一个委员会认证的临床肾脏病理学家，是人类肾小球细胞培养的专家。 从活组织检查和尿液中分离的上皮。所有导师均与陈博士建立专业合作关系。 因此，我们投资于本文概述的科学和专业目标的成功。