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: 9086496
• 负责人: LaTonya J Hickson
• 金额: $ 16.08万
• 依托单位: MAYO CLINIC ROCHESTER
• 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 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9086496
• 关键词: Activities of Daily Living; Acute Renal Failure with Renal Papillary Necrosis; Adipose tissue; Advisory Committees; Aftercare; Age; Aging; American; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Autologous; Basic Science; Biologic Characteristic; Biopsy; Blood; Blood Vessels; Blood flow; Cell Aging; Cell Cycle Arrest; Cell physiology; Cells; Cellular Structures; Chronic; Chronic Kidney Failure; Clinic; Clinical Research; Clinical Sciences; Clinical Trials; Clinical trial protocol document; Collection; Cost Savings; Data; Development Plans; Diabetes Mellitus; Diabetic Nephropathy; Dialysis procedure; Disease; Disease model; Drug usage; Eligibility Determination; End stage renal failure; Enrollment; Environment; Functional disorder; Funding; Future; Gender; Glomerular Filtration Rate; Goals; Harvest; Health; Hypertension; Impairment; In Vitro; Incubated; Inflammatory; Injury; Institution; Intervention; Investigation; Kidney Diseases; Kidney Failure; Kidney Transplantation; Knowledge; Laboratories; Laboratory Research; Master' s Degree; Measurement; Measures; Mentors; Mesenchymal; Mesenchymal Stem Cells; Methods; Microalbuminuria; Modeling; Morbidity - disease rate; Natural regeneration; Nephrology; Obesity; Outcome; Oxidative Stress; Patients; Performance; Pharmaceutical Preparations; Phase I Clinical Trials; Phenotype; Pilot Projects; Plague; Population; Prevalence; Property; Protocols documentation; Publications; Regenerative Medicine; Renal function; Renin-Angiotensin-Aldosterone System; Research; Research Infrastructure; Research Personnel; Resistance; Rotation; Safety; Site; Societies; Stem cell transplant; Stem cells; Therapeutic; Time; Translational Research; Transplantation; Tube; United States; Uremia; Urine; abdominal fat; abstracting; career; career development; cell age; clinical epidemiology; design; diabetic; effective intervention; effective therapy; experience; glomerulosclerosis; implantation; improved; in vivo; innovation; kidney repair; kidney vascular structure; member; migration; multidisciplinary; novel; novel therapeutics; paracrine; pre-clinical; preconditioning; prevent; public health relevance; regenerative; senescence; skills; stem cell therapy; symposium; tissue oxygenation; tool

 DESCRIPTION (provided by applicant): I am a practicing nephrologist and Co-Director of the Chronic Kidney Disease (CKD) clinic at Mayo Clinic, and member of the American Society of Nephrology Dialysis Advisory Group. My research to date has examined patient-important outcomes in dialysis, hypertension, and kidney transplant populations. 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). In my quest to improve the lives of patients with CKD, 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 a Master's degree in Clinical and Translational Science with a focus on regenerative medicine. My long-term goal is to become a leader in Regenerative Nephrology and an independent, productive clinician-investigator. My career development plan during the K23 period entails laboratory rotations, on-site and off-site clerkships in centers for regenerative medicine, individualized coursework, publications, collaborative network building, exposure through abstract presentations at national conferences, and experience with clinical trial protocol design and implementation. These endeavors 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. DN is the most prevalent cause of CKD and resistant to most interventions aimed at preventing progression. However, recent advances in regenerative medicine of adipose tissue-derived mesenchymal stromal/stem cell (MSC) transplantation offer hope. MSCs are non-embryonic stem cells with anti-fibrotic, anti-inflammatory, and pro-angiogenic paracrine activity that improve regeneration in DN models. However, patient-specific factors such as aging, obesity, uremia, and diabetes may decrease cellular function by inducing cellular senescence. 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. Our exciting new data reveal that cellular senescence, a central mechanism limiting MSC functional capacity, may be treatable through senolytic drugs that selectively eliminate senescent cells. In accordance, we showed that eradicating senescent cells improves stem cell function in animal models. Therefore, we plan to examine senolytic therapy as a potential in vivo preconditioning method to improve stem cell function. Our central hypothesis underlying the proposed studies is that adipose tissue-derived MSC obtained from patients with DN show increased senescence and decreased functionality, which can be ameliorated, both in vitro and in vivo, using drugs that clear senescent cells. This hypothesis will be pursued in 3 specific aims. First, we will compare cellular senescence and functionality in adipose tissue-derived MSC from patients with DN [estimated glomerular filtration rate (eGFR) 15-60 mL/min/1.73m2] to MSC from age- and gender-matched controls. Second, to determine the reversibility of DN-MSC dysfunction, we will incubate cells with senolytic agents in vitro and assess DN-MSC senescent cell clearance and function thereafter. Third, to examine the effect of senolytic agents on DN-MSC function in vivo, we will conduct a pilot study wherein DN patients (eGFR 15-45 mL/min/1.73m2) will receive senolytic drugs, and MSC senescence and function will be measured at baseline and 14 days after treatment with comparison to untreated controls. For each of these studies, DN patients will undergo 1-2 abdominal fat biopsies for MSC harvesting. Additional examinations will include blood and urine collection for diabetes, kidney function, and CKD-related measurements. Significance: Developing a safe and effective therapy to delay DN progression could reduce morbidity associated with dialysis, offer a better treatment option to a population often deferred for kidney transplantation, and produce extensive cost savings. These novel studies will advance the knowledge of the effects of cellular senescence on MSC, and help develop pre-screening protocols to optimize enrollment in trials using autologous MSC transplantation for DN. Furthermore, 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 the progression of DN. As a nephrologist, I am passionate about improving the lives of patients with CKD through innovative research. I believe my determination, clinical and research background, optimal and supportive institutional environment, and outstanding multidisciplinary mentoring and advisory team in combination with the protected time and funding from the K23 will propel me toward my goals of becoming an independent clinician-investigator and bringing stem cell therapy to patients with DN.

 个人简介(申请人提供)：我是执业肾科医生，梅奥诊所慢性肾脏病(CKD)诊所的联席主任，美国肾病学会透析顾问组成员。到目前为止，我的研究已经检查了透析、高血压和肾移植人群中患者的重要结果。我将利用从我的临床和流行病学背景中获得的技能，将拟议的基础研究调查带入真正的糖尿病肾病(DN)患者的转化性研究。在我的 为了改善CKD患者的生活，我组建了一个由多学科导师组成的团队，他们将提供执行拟议研究所需的指导、基础设施和工具。我目前的职业目标是获得实验室研究技能、临床试验经验、再生医学知识基金，以及临床和转化学硕士学位，重点是再生医学。我的长期目标是成为再生肾病领域的领导者，成为一名独立、高效的临床医生和研究员。我在K23期间的职业发展计划包括实验室轮换、再生医学中心的现场和非现场助理工作、个性化的课程工作、出版物、合作网络的建立、通过在国家会议上的抽象演讲而曝光，以及临床试验方案设计和实施的经验。这些努力将为我提供过渡到独立所需的基石。我得到了我的部门、部门和机构的最强有力的支持。在拟议的研究中，我将探索一种新的治疗平台的可行性，我相信这种平台可以改变病程，改善糖尿病肾病患者的生活。糖尿病肾病是一种毁灭性的疾病，几乎没有治疗选择。糖尿病肾病是慢性肾脏病最常见的原因，对大多数旨在预防进展的干预措施具有抵抗力。然而，脂肪组织来源的间充质干细胞(MSC)移植的再生医学最近的进展为我们带来了希望。MSCs是一种非胚胎干细胞，具有抗纤维化、抗炎和促血管生成旁分泌活性，可促进糖尿病肾病模型的再生。然而，患者特有的因素，如衰老、肥胖、尿毒症和糖尿病，可能会通过诱导细胞衰老而降低细胞功能。衰老是一种不可逆转的细胞周期停滞，它会产生一种促炎症的分泌表型，从而损害邻近细胞的功能。因此，糖尿病肾病患者衰老细胞负荷的增加可能严重损害MSC的功能，并成为成功进行自体MSC移植的障碍。我们的总体目标是确定和优化糖尿病肾病患者骨髓间充质干细胞的功能特性，使这些患者在未来的干细胞移植临床试验中受益。我们令人兴奋的新数据显示，细胞衰老是限制MSC功能能力的核心机制，可能可以通过选择性消除衰老细胞的衰老药物来治疗。因此，我们在动物模型中表明，根除衰老细胞可以改善干细胞功能。因此，我们计划研究感觉神经溶解疗法作为一种潜在的体内预适应方法来改善干细胞功能。我们提出的研究的中心假设是，从糖尿病肾病患者获得的脂肪组织来源的MSC显示出衰老增加和功能降低，这一点在体外和体内都可以通过使用清除衰老细胞的药物来改善。这一假设将在三个具体目标中得到追求。首先，我们将比较来自糖尿病肾病患者[估计肾小球滤过率(EGFR)15-60毫升/分钟/1.73m2]的脂肪组织来源的MSC和年龄和性别匹配的对照组的MSC的细胞衰老和功能。其次，为了确定糖尿病肾病间充质干细胞功能障碍的可逆性，我们将在体外将细胞与感觉剂孵育，然后评估糖尿病肾病-间充质干细胞衰老细胞的清除和功能。第三，为了研究增老剂对糖尿病肾病患者体内骨髓间充质干细胞功能的影响，我们将进行一项先导性研究，糖尿病肾病患者(EGFR 15-45毫升/分钟/1.73平方米)将接受促衰老药物治疗，并在治疗前和治疗后14天测量骨髓间充质干细胞的衰老和功能，并与未经治疗的对照组进行比较。对于这些研究中的每一项，糖尿病肾病患者将接受1-2次腹部脂肪活检以获取MSC。其他检查将包括糖尿病的血液和尿液采集、肾功能和CKD相关测量。意义：开发一种安全有效的延缓糖尿病肾病进展的疗法可以减少与透析相关的发病率，为经常推迟进行肾移植的人群提供更好的治疗选择，并产生广泛的成本节约。这些新颖的研究将促进对细胞衰老对MSC影响的了解，并有助于开发预筛选方案，以优化使用自体MSC移植治疗糖尿病肾病的试验的登记。此外，拟议的研究探索了一种创新的方法来对MSC及其有害的微环境进行预适应，并有助于开发一种全新的治疗策略来延缓糖尿病肾病的进展。作为一名肾病医生，我热衷于通过创新研究来改善CKD患者的生活。我相信，我的决心、临床和研究背景、最佳和支持性的机构环境、出色的多学科指导和咨询团队，再加上K23提供的保护时间和资金，将推动我朝着成为一名独立的临床医生兼研究人员的目标前进，并将干细胞疗法带给糖尿病肾病患者。