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.

 描述（由应用程序提供）：我是Mayo诊所的慢性肾脏病（CKD）诊所的实践肾脏科医生和联合导演，也是美国肾脏病学会透析咨询小组的成员。迄今为止，我的研究检查了透析，高血压和肾脏移植人群中最重要的结果。我将利用我的临床和流行病学背景中获得的获得的技能，将拟议的基础研究调查带入针对糖尿病性肾病（DN）患者的真正翻译研究。在我的 寻求改善CKD患者的生活，我组建了一个多学科的导师团队，他们将提供指导，基础设施以及拟议研究所需的工具。我的直接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科学硕士学位，重点是再生医学。我的长期目标是成为再生肾脏病和独立的生产临床评估剂的领导者。我的职业发展计划在K23时期实验实验室的轮换，现场和现场离合器中心的再生医学中心，个性化课程，出版物，协作网络建设，通过摘要在国家会议上通过抽象演讲进行曝光以及具有临床试验协议设计和实施的经验。这些努力将为我提供过渡到独立所需的基础。我的部门，部门和机构得到了强有力的支持。在拟议的研究中，我将探讨一个新型治疗平台的可行性，我认为它可能会改变疾病的进程并改善DN患者的生活，DN是一种毁灭性疾病，几乎没有治疗选择。 DN是CKD的最普遍原因，并且对大多数旨在防止进展的干预措施具有抵抗力。但是，脂肪组织衍生的间充质基质/干细胞（MSC）移植的再生医学的最新进展为人们提供了希望。 MSC是具有抗纤维化，抗炎和促血管生成旁分泌活性的非胚胎干细胞，可改善DN模型的再生。但是，患者特异性因素（例如衰老，肥胖，尿素和糖尿病）可能会通过诱导的细胞感应降低细胞功能。 Sensence是一种不可逆转的细胞周期停滞，它会产生促进感染的秘书表型，从而损害附近的细胞功能。因此，DN中的感官细胞燃烧增加可能会大大损害MSC功能，并成为成功自体MSC移植的障碍。我们的总体目标是表征和优化DN中MSC的功能性能，以使这些患者使用干细胞移植中的临床试验中的未来入学受益。我们令人兴奋的新数据表明，通过有选择性地消除感觉细胞的鼻溶液药物可以治疗细胞感应，一种限制MSC功能能力的中心机制。根据，我们表明消除感觉细胞可以改善动物模型中的干细胞功能。因此，我们计划将塞溶性疗法作为一种潜在的体内预处理方法来改善干细胞功能。我们提出的研究的基本假设是，从DN患者获得的脂肪组织衍生的MSC显示出使用清除感应细胞的药物，在体外和体内都可以改善功能降低和功能降低。该假设将以3个具体目标提出。首先，我们将从DN [估计的肾小球滤过率（EGFR）15-60 mL/min/1.73m2]的脂肪组织衍生的MSC中的细胞感应和功能与来自年龄和性别匹配的对照组的MSC进行比较。其次，为了确定DN-MSC功能障碍的可逆性，我们将在体外与鼻溶剂孵育细胞，并评估DN-MSC Senscent细胞清除率及其功能。第三，为了检查鼻溶剂对体内DN-MSC功能的影响，我们将进行一项试点研究，其中DN患者（EGFR 15-45 ml/min/min/1.73m2）将接受鼻溶液药物，并且在基线和14天后，将在基础上测量MSC的感应和功能，并在与未培养的对照组中进行比较后进行14天。对于这些研究，DN患者将进行1-2个腹部脂肪活检以进行MSC收集。其他检查将包括用于糖尿病，肾功能和与CKD相关的测量的血液和尿液。意义：开发一种安全有效的疗法来延迟DN进展，可以降低与透析相关的发病率，为经常推迟肾脏移植的人群提供更好的治疗选择，并节省大量成本。这些新的研究将提高细胞感应对MSC的影响的了解，并有助于制定筛查方案，以优化使用自体MSC移植DN的试验入学。此外，拟议的研究探讨了一种创新的方法，用于预处理MSC及其微妙的微环境，并有助于制定一种完全新颖的治疗策略，以延迟DN的发展。肾脏科医生，我热衷于通过创新研究改善CKD患者的生活。我相信我的决心，临床和研究背景，最佳和支持的机构环境以及出色的多学科指导和咨询团队以及K23受保护的时间和资金将使我朝着成为独立的临床评估剂，并将DN患者带给患者的独立临床疗法。