Mesenchymal stem cell senescence in diabetic nephropathy

糖尿病肾病中的间充质干细胞衰老

• 批准号: 10275178
• 负责人: LaTonya J Hickson
• 金额: $ 5.25万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10275178
• 关键词: Activities of Daily Living; Adipose tissue; Aftercare; Anti-Inflammatory Agents; Autologous; Basic Science; Blood; Cell Aging; Cell Cycle Arrest; Cell physiology; Cells; Clinic; Clinical Trials; Collection; Development Plans; Diabetes Mellitus; Diabetic Nephropathy; Disease; Drug usage; Enrollment; Funding; Future; Gender; Goals; Health; Impairment; In Vitro; Incubated; Inflammatory; Infrastructure; Injury to Kidney; Institution; Investigation; Kidney Diseases; Kidney Failure; Knowledge; Laboratory Research; Measurement; Measures; Mentors; Mesenchymal; Mesenchymal Stem Cells; Methods; Modeling; Natural regeneration; Nephrology; Patients; Performance; Pharmaceutical Preparations; Phenotype; Pilot Projects; Property; Regenerative Medicine; Renal function; Research Personnel; Stem cell transplant; Therapeutic; Translational Research; United States; Urine; career; career development; cell age; clinical epidemiology; experience; improved; in vivo; innovation; kidney repair; multidisciplinary; novel therapeutic intervention; novel therapeutics; paracrine; preconditioning; regenerative; senescence; skills; stem cell function; stem cells; tool

PROJECT SUMMARY/ABSTRACT I am a practicing nephrologist at Mayo Clinic and I will use the acquired skills from my clinical and epidemiology background to bring the proposed basic research investigations into truly translational research for patients with diabetic nephropathy (DN). I have assembled a multidisciplinary team of mentors who will provide guidance, infrastructure, and tools needed for performance of the proposed studies. My immediate career goal is to gain laboratory research skills, clinical trial experience, regenerative medicine fund-of- knowledge, and regenerative medicine coursework. My long-term goal is to become a leader in Regenerative Nephrology and an independent, productive clinician-investigator. My career development plan will provide me with the building blocks needed to transition into independence. I have the strongest support from my division, department, and institution. In the proposed studies, I will explore the feasibility of a novel therapeutic platform that I believe may change the course of disease and improve the lives of patients with DN, a devastating disease with few therapeutic options. Mesenchymal stromal/stem cell (MSC) transplantation offers hope. MSCs are non-embryonic stem cells with anti-fibrotic, anti-inflammatory, and pro-angiogenic paracrine activity that improve regeneration in DN models. Senescence is an irreversible cell cycle arrest, which generates a pro-inflammatory secretory phenotype that impairs neighboring cell function. Hence, increased senescent cell burden in DN may substantially compromise MSC function and become a barrier to successful autologous MSC transplantation. Our overall goal is to characterize and optimize the functional properties of MSC in DN to allow these patients to benefit from future enrollment in clinical trials using stem cell transplantation. A central mechanism limiting MSC functional capacity, may be treatable through senolytic drugs that selectively eliminate senescent cells. We will examine senolytic therapy as a potential in vivo preconditioning method to improve stem cell function. Our central hypothesis is that adipose-derived MSC obtained from DN patients show increased senescence and decreased functionality, which can be ameliorated, both in vitro and in vivo, using drugs that clear senescent cells. First, we will compare cellular senescence and functionality in MSC from DN patients to MSC from age- and gender-matched controls. Second, we will incubate cells with senolytic agents in vitro and assess DN-MSC senescent cell clearance and function thereafter. Third, we will conduct a pilot study wherein DN patients will receive senolytic drugs, and MSC senescence and function will be measured at baseline and 14 days after treatment. Additional examinations will include blood and urine collection for kidney function and injury measurements. The proposed studies explore an innovative approach for preconditioning MSC and their deleterious microenvironment, and aid in developing a completely novel therapeutic strategy to delay DN progression.

项目概要/摘要 我是梅奥诊所的一名执业肾脏病专家，我将运用从临床和临床中获得的技能 流行病学背景，将拟议的基础研究调查转化为真正的转化研究 适用于糖尿病肾病（DN）患者。我组建了一个多学科的导师团队，他们将 提供执行拟议研究所需的指导、基础设施和工具。我的即时 职业目标是获得实验室研究技能、临床试验经验、再生医学基金- 知识和再生医学课程。我的长期目标是成为再生领域的领导者 肾脏病学和一位独立、富有成效的临床医生研究员。我的职业发展计划将为我提供 具备过渡到独立所需的基础。我得到了我的部门最强有力的支持， 部门、机构。在拟议的研究中，我将探索新型治疗平台的可行性 我相信这可能会改变疾病进程并改善 DN 患者的生活，DN 是一种毁灭性的疾病 几乎没有治疗选择的疾病。间充质基质/干细胞（MSC）移植带来了希望。 MSC 是非胚胎干细胞，具有抗纤维化、抗炎和促血管生成旁分泌活性 改善 DN 模型的再生。衰老是一种不可逆的细胞周期停滞，会产生 损害邻近细胞功能的促炎分泌表型。因此，衰老细胞增多 DN 的负担可能会严重损害 MSC 功能并成为成功自体同源的障碍 间充质干细胞移植。我们的总体目标是表征和优化 MSC 的功能特性 DN 让这些患者能够从未来参加干细胞临床试验中受益 移植。限制 MSC 功能能力的中心机制可通过 senolytic 治疗 选择性消除衰老细胞的药物。我们将研究 senolytic 疗法作为一种潜在的体内疗法 改善干细胞功能的预处理方法。我们的中心假设是脂肪来源的 MSC 从 DN 患者获得的细胞显示衰老增加和功能下降，这可以 使用清除衰老细胞的药物可以在体外和体内得到改善。首先我们来比较一下 从 DN 患者到年龄和性别匹配的 MSC 的细胞衰老和功能 控制。其次，我们将细胞与衰老抑制剂一起体外培养并评估DN-MSC衰老细胞 此后的清除和功能。第三，我们将进行一项试点研究，其中 DN 患者将接受 将在基线和治疗后 14 天测量 MSC 的衰老和功能。 其他检查将包括收集血液和尿液以进行肾功能和损伤测量。 拟议的研究探索了一种预处理 MSC 及其有害物质的创新方法 微环境，并有助于开发一种全新的治疗策略来延缓 DN 进展。