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: 10593049
• 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 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593049
• 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; Board Certification; 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; Darkness; Development; Development Plans; Diabetes Mellitus; Doctor of Philosophy; Elderly; Environment; Epithelial Cells; Epithelium; Excretory function; Filtration; Future; Genus Hippocampus; Glomerular capsule structure; Goals; Health; High Fat Diet; Human; Hypertension; In Vitro; Injury; Injury to Kidney; Inner mitochondrial membrane; Intervention; Investments; K-Series Research Career Programs; Kidney; Kidney Diseases; Lesion; Life; Light; Measurement; Mediating; Membrane; Mentors; Mesenchymal; Methods; Mitochondria; 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; 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; healing; improved; in vivo; injured; kidney cell; man; meetings; mesangial cell; mitochondrial dysfunction; multidisciplinary; peroxidation; podocyte; postmitotic; 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.

摘要：线粒体保护以得出扩大的老年肾肾小球祖细胞 候选人：该K01职业发展奖申请描述了研究和培训活动 Mariya T. Sweetwyne博士大学病理学系的肾细胞生物学家 华盛顿，西雅图。她的直接职业目标是将她既定的肾脏生物学培训结合在一起 在细胞衰老的生物学中新获得和正在进行的培训。长期，她打算建造一个 独立研究计划的重点是制定干预措施以改善细胞衰老的影响 在慢性和急性肾脏肾小球疾病上。在此应用程序中，Sweetwyne博士的提案特定于 旨在确定线粒体功能障碍对衰老肾小球上皮细胞的病理的作用。 研究：肾脏衰老的标志是肾小球过滤单元的纤维化变化，这导致 随着年龄的增长，增加了慢性肾脏疾病的风险。 Sweetwyne博士的先前研究 等。证明用四肽elamipretide（SS-31/bendavia）治疗旧小鼠以保存 线粒体内膜结构显着降低了肾脏衰老的肾小球损伤，表明 老年肾脏可塑性的一个关键在于线粒体健康。该提议以这些发现为基础 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（AIM 2） 线粒体改善如何导致观察到的肾小球感染降低（AIM 3）和 这些已知的增强是否会影响老年和衰老的肾脏的再生潜力 小鼠和人的祖细胞。职业发展计划：该提议为Sweetwyne博士的矮小服务提供服务 和长期目标通过在三个关键领域建立衰老生物学的基准专业知识：（1） 线粒体能量学的评估，（2）蛋白质组学的利用和（3）原代的分离和培养 人尿液来源的祖细胞。专业的学术发展活动包括：正式研究生 衰老生物学的课程工作，在国家科学会议上的研究表现和定期 与职业导师的预定会议。环境：Sweetwyne博士在 华盛顿大学（UW）非常出色。她的多学科指导团队已完成 是线粒体能量学，衰老生物学或肾脏科的专家。 Sweetwyne博士的校长 导师Rabinovitch博士被公认为是衰老领域的领导者，并成功指导了多个 通过K01和K99/R00奖的受训者。 UW放射学的Co-Mentor David Marcinek博士是专家 衰老或受伤的肌肉中的线粒体能量和氧化应激。联合委托人Behzad Najafian博士 UW病理学是董事会认证的临床肾脏病理学家，是人类肾肾小球文化的专家 从活检和尿液中分离出的上皮。所有导师都与博士建立了专业合作。 Sweetwyne，因此投资于这里概述的科学和专业目标的成功。