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: 9977071
• 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/9977071
• 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; Epithelium; 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; 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; regenerative; 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：线粒体保护衍生扩大的老化肾小球祖细胞 候选人：这份 K01 职业发展奖申请描述了以下领域的研究和培训活动： Mariya T. Sweetwyne 博士，英国大学病理学系肾细胞生物学家 华盛顿，西雅图，她的近期职业目标是将她在肾脏生物学方面的培训与结合起来。 从长远来看，她打算建立一个新的和持续的细胞衰老生物学培训。 独立研究计划专注于开发干预措施以改善细胞衰老的影响 在本申请中，Sweetwyne 博士提出了针对慢性和急性肾小球疾病的具体建议。 旨在确定线粒体功能障碍对衰老肾小球上皮细胞病理学的作用。 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 Sweetwyne 博士之前的研究表明，随着年龄的增长，患慢性肾病的风险会增加。 等人证明，用四肽 Elamipretide (SS-31/Bendavia) 治疗老年小鼠，可以保留 线粒体内膜结构显着减少了肾脏衰老引起的肾小球损伤，表明 老年人肾脏可塑性的关键在于线粒体健康。这项提议建立在这些发现的基础上。 询问：（目标 1）特定肾小球上皮细胞中线粒体功能的哪一方面得到改善，（目标 2） 线粒体改善如何导致观察到的肾小球细胞衰老减少（目标 3）以及 这些已知的增强功能是否会影响衰老和衰竭肾脏的再生潜力 小鼠和人类的祖细胞职业发展计划：该提案符合 Sweetwyne 博士的简短建议。 通过在三个关键领域建立衰老生物学的基础专业知识来实现​​长期目标：(1) 线粒体能量学的评估，（2）蛋白质组学的利用，以及（3）原代细胞的分离和培养 人类尿液来源的祖细胞专业学术发展活动包括： 正式研究生。 衰老生物学的课程作业、在国家科学会议上的研究报告和例行公事 与职业导师的预定会议环境：Sweetwyne 博士在学院接受培训的环境。 华盛顿大学 (UW) 的多学科导师团队由资深人士组成。 Sweetwyne 博士的校长是线粒体能量学、衰老生物学或肾病学方面的专家。 导师 Rabinovitch 博士被公认为老龄化领域的领导者，并已成功指导了多位 获得 K01 和 K99/R00 奖项的学员，华盛顿大学放射科的联合导师 David Marcinek 博士是这方面的专家。 衰老或受伤肌肉的线粒体能量学和氧化应激。 Behzad Najafian 博士。 华盛顿大学病理学是经过委员会认证的临床肾脏病理学家，是人类肾小球培养方面的专家 从活检和尿液中分离出的上皮细胞。所有导师都与 Dr. 建立了专业合作关系。 Sweetwyne 因此致力于本文概述的科学和专业目标的成功。