Stem Cell-Based Therapy of Chronic Kidney Disease

慢性肾脏病的干细胞疗法

基本信息

批准号：
8821217
负责人：
Christof Westenfelder
金额：
--
依托单位：
VA SALT LAKE CITY HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8821217
关键词：
Acute Kidney Failure Acute Renal Failure with Renal Papillary Necrosis Address Adipose tissue Adult Adverse effects Affect Albuminuria Allogenic Anemia Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apoptotic Blood Glucose Blood Pressure Bone Marrow Cardiac Surgery procedures Caring Cell Therapy Cells Centers for Disease Control and Prevention (U.S.)Cholesterol Chronic Chronic Kidney Failure Clinic Clinical Comorbidity Complication Data Development Diabetes Mellitus Diabetic Nephropathy Dialysis procedure Disease Disease Progression Disease model Dose End stage renal failure Enrollment Fatty acid glycerol esters General Population Goals Guidelines Health Healthcare Systems Heart Diseases Hemodialysis Hospitalization Hypertension Incidence Individual Infection Injury Intervention Intravenous Kidney Kidney Transplantation Lead Mediator of activation protein Medical Mesenchymal Stem Cells Modality Modeling Monitor Myocardial Infarction Nephrectomy Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Outcome Patients Phase I Clinical Trials Phase II Clinical Trials Pilot Projects Population Postoperative Period Prevention Proteinuria Protocols documentation Rat-1 Rattus Renal function Research Research Design Risk Small Interfering RNA Source Staging Stem cells Stroke Study Subject Technology Testing Therapeutic Therapeutic Effect Time Tissues Translating Translations Treatment Efficacy Treatment Protocols Veterans Work World Health Organization Zucker Rats adult stem cell base clinical application combat cost design diabetic effective therapy epidemiologic data experience glomerulosclerosis high risk improved knock-down male mortality non-diabetic novel pre-clinical preclinical study prevent protective effect public health relevance stem cell therapy tool

项目摘要

DESCRIPTION (provided by applicant): SIGNIFICANCE and LONG-TERM OBJECTIVE: Chronic kidney disease (CKD), a progressive disorder that results in end stage renal disease (ESRD) requiring chronic hemodialysis or renal transplant, affects 400 million individuals globally and 26 million in the US. In ~50% of all cases CKD is caused by type 2 diabetes mellitus (T2DM). CKD and its comorbidities constitute a major financial burden to the health care system, warranting the development of new therapies to arrest or ameliorate the progression of the disease. Data obtained from this proposal are expected eventually to translate into clinical applications that will benefit those afflicted with CKD. RATIONALE and HYPOTHESES: We demonstrated that administration of allogeneic, bone marrow- derived mesenchymal stem cells (MSCs) to rats 1) affords renoprotection from Acute Kidney Injury (AKI), even with underlying CKD, and 2) prevents progression of CKD. This is achieved through MSC's anti- inflammatory and trophic anti-apoptotic, mitogenic and vasculoprotective actions. Results from our Phase I Clinical Trial, wherein at-risk cardiac surgery patients, the majority of whom had underlying CKD, were administered MSCs to prevent post-operative AKI, confirm those of preclinical studies, and indicate MSC administration is a safe, effective preventative therapy for AKI and both progression to CKD and of CKD itself. A Phase II Clinical Trial is currently enrolling study subjects. We hypothesize, therefore, that allogeneic MSC therapy effectively treats rats with CKD induced by 5/6th nephrectomy or T2DM (male Zucker, obese, rats), arresting or slowing the progression of CKD. Indeed, our preliminary work in the 5/6th nephrectomy CKD model in rats indicates that MSC administration given early or late post induction of CKD is effective, to variable degrees, in improving several manifestations of this form of CKD, i.e., systolic blood pressure, renal function, albuminuria and glomerular sclerosis. SPECIFIC AIMS: The present work is designed to fully investigate the therapeutic utility of adult stem cells for the treatment of CKD and underlying diabetes mellitus in rat models. Specifically, Aim 1. will test and develop optimal earl and late stem cell based intervention protocols in rats with CKD due to 5/6th nephrectomy or T2DM; Aim 2, will elucidate the mediator mechanisms that underlie the kidney protective effects of stem cells in rats with CKD caused by 5/6th nephrectomy or T2DM; and Aim 3 will assess whether the therapy found to be optimally effective in 5/6th Nephrectomy induced CKD (Specific Aim 1) is equally effective in CKD of diabetic Zucker rats. RESEARCH DESIGN and METHODS: Specific Aim 1 (SA): Using rat 5/6 nephrectomy CKD models, the optimal therapeutic efficacy of repeated and different intravenous cell doses, given early and/or late in the course of CKD will be determined by monitoring, over time or at study end, alterations in GFR, proteinuria, glomerulosclerosis, blood pressure, and other variables. SA 2: Mediator mechanisms that correlate with the therapeutic effects of MSCs that are documented in the studies of SA 1 are investigated, using as a guideline the anti-inflammatory, anti-fibrotic, anti-thrombotic and trophic actions of MSC that have been identified in AKI and other organ injuries. The importance of individual therapeutically effective factors expressed by MSCs will be further corroborated by knocking down their expression in MSCs (siRNA) or by blocking their identified mechanisms of actions. SA 3: It will be tested in male, obese, diabetic Zucker rats, whether MSC treatment improves blood sugar control per se and thereby the development of and/or progression of diabetic nephropathy.

描述（由申请人提供）：意义和长期目标：一种进行性疾病，是一种进行性疾病，导致终结阶段肾脏疾病（ESRD）需要慢性血液透析或肾移植，在美国影响4亿个人，在美国影响2600万人。在所有情况下，在所有情况下，CKD是由2型糖尿病（T2DM）引起的。 CKD及其合并症构成了医疗保健系统的重大财务负担，保证开发新疗法以阻止或改善该疾病的发展。预计从该提案中获得的数据最终将转化为临床应用，这些应用将使患有CKD折磨的人受益。基本原理和假设：我们证明，同种异体骨髓衍生的间充质干细胞（MSC）的给药1）可从急性肾损伤（AKI）进行肾脏侵蚀，即使是基本的CKD，并且2）预防CKD的进展。这是通过MSC的抗炎和营养抗凋亡，有丝分裂和血管保护作用来实现的。我们的I期临床试验的结果是，在危险的心脏手术患者（大多数基础CKD）的情况下，使用了MSC，以防止术后AKI，确认临床前研究的AKI，并表明MSC给药是AKI的安全，有效的预防治疗，对AKI和CKD的进展和CKD和CKD本身是一种安全的预防治疗。 II期临床试验目前正在招募研究对象。因此，我们假设同种异体MSC治疗可有效治疗由5/6肾切除术或T2DM诱导的CKD（雄性Zucker，肥胖，肥胖，大鼠），从而阻止或减慢CKD的进展。实际上，我们在大鼠第5/6肾切除术CKD模型中的初步工作表明，CKD诱导后提前或晚期给药的MSC给药在改善这种形式的CKD的几种表现方面是有效的，即，收缩压，肾脏压力，白蛋白尿和肾小球层面。具体目的：目前的工作旨在充分研究大鼠模型中成年干细胞治疗CKD和潜在糖尿病的治疗效用。具体而言，AIM 1。将由于5/6肾切除术或T2DM而在患有CKD大鼠的大鼠中测试和开发最佳的伯爵和晚期基于干细胞的干预方案； AIM 2，将阐明由5/6肾切除术或T2DM引起的CKD大鼠干细胞肾脏保护作用的介体机制； AIM 3将评估发现在5/6肾切除术诱导的CKD（特定AIM 1）中发现的治疗是否在糖尿病扎克大鼠的CKD中同样有效。 RESEARCH DESIGN and METHODS: Specific Aim 1 (SA): Using rat 5/6 nephrectomy CKD models, the optimal therapeutic efficacy of repeated and different intravenous cell doses, given early and/or late in the course of CKD will be determined by monitoring, over time or at study end, alterations in GFR, proteinuria, glomerulosclerosis, blood pressure, and other variables. SA 2：研究了与SA 1研究中记录的MSC的治疗作用相关的介体机制，该指南用作指南，抗炎，抗纤维化，抗纤维化，抗直联，抗血栓形成和营养性MSC在AKI和其他器官损伤中已鉴定出来。 MSC表达的个人治疗有效因素的重要性将通过击倒其在MSC（siRNA）中的表达或阻止其确定的作用机制来进一步证实。 SA 3：它将在雄性，肥胖，糖尿病扎克大鼠中进行测试，无论MSC治疗是否可以改善血糖控制本身，从而发展和/或糖尿病性肾病的发展和/或进展。