Extracellular vesicle-based senotherapeutics for aging diabetic kidneydisease

基于细胞外囊泡的老年糖尿病肾病治疗药物

• 批准号: 10655273
• 负责人: LaTonya J Hickson
• 金额: $ 57.89万
• 依托单位: MAYO CLINIC JACKSONVILLE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655273
• 关键词: Acceleration; Address; Adverse event; Affect; Age; Aging; Animal Model; Anti-Inflammatory Agents; Biological Models; Biological Response Modifier Therapy; Cell Aging; Cells; Characteristics; Chronic Kidney Failure; Clinic; Clinical; Clinical Trials; Combined Modality Therapy; Dasatinib; Data; Deterioration; Diabetes Mellitus; Diabetic Nephropathy; Disease; Disease Progression; Disease Resistance; Disease model; Dose; End stage renal failure; Ensure; Filtration; Future; Goals; Growth; Human; Hyperglycemia; In Vitro; Incidence; Individual; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury to Kidney; Intervention; Kidney; Kidney Diseases; Kidney Failure; Knowledge; Longevity; Macrophage; Mediating; Methods; MicroRNAs; Mus; Obesity; Obesity Epidemic; Onset of illness; Organ; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Performance; Persons; Predisposition; Process; Prognosis; Quercetin; Source; Sterility; Subgroup; System; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Tissues; Treatment Efficacy; United States; Uremia; Work; age related; aged; aging population; chemokine; clinical translation; cytokine; delivery vehicle; diabetic; digital; extracellular vesicles; glucose transport; glycemic control; immune modulating agents; improved; insight; kidney dysfunction; kidney repair; mesenchymal stromal cell; mouse model; nano-string; novel; novel strategies; novel therapeutics; obese person; pre-clinical; secretory protein; senescence; side effect; small molecule; success; targeted treatment

Project Summary The rise in an aging population plagued by obesity and diabetes mellitus is projected to render exponential growth in diabetic kidney disease (DKD). Hence, therapeutic interventions that halt aging-related kidney changes and DKD must be rigorously pursued. Maladaptive inflammation drives DKD onset, and proinflammatory cytokines and chemokines activate macrophages leading to kidney infiltration and poor renal prognosis. Yet, inflammation remains a major unaddressed injurious pathway in DKD. We and others demonstrated that maladaptive inflammation in DKD patients and animal models is associated with increased cellular senescence and kidney dysfunction. Thus, decreasing senescence through senotherapeutics, such as, small molecule drugs or cell-derived components, may halt DKD and age-related kidney deterioration. Therefore, there is an urgent need to develop a therapeutic armamentarium targeting the multifaceted pathogenesis (inflammation and cell senescence) of DKD to extend healthy lifespan. We and others demonstrated that mesenchymal stromal cells (MSCs) suppress inflammatory responses through secretion of extracellular vesicles (EVs) containing biologically active cargo, primarily microRNAs (miRNAs), and reduce senescent burden and extend lifespan in aging mouse models. Although the therapeutic activity of MSC-EVs has previously been assessed in aging and inflammatory disease models, the effects of these biotherapeutics on inflammation and senescence in aging DKD remain unexplored. Our preliminary results indicate that MSC-EVs: (i) reduce senescence pathways, macrophage infiltration, and kidney injury in murine DKD and (ii) can be loaded with small molecule drugs for combination therapy. Additionally, our recent study demonstrated, for the first time, that senolytic drugs, dasatinib and quercetin, reduce senescent cell abundance in humans and improve kidney injury following senescent cell clearance in mouse models. We hypothesize that EVs have anti-inflammatory and senotherapeutic effects in aging DKD, that can be further enhanced by co-delivery of senolytic drugs. To address this central hypothesis, we will determine the effects of EV miRNAs on senescence and inflammation in vitro (Aim 1), assess the effects of EVs from several sources in a mouse model of aging DKD (Aim 2), and evaluate the performance of EVs as drug delivery vehicles for dasatinib and quercetin (Aim 3). To ensure the technical success of this study, we have assembled a team with complementary expertise in aging, DKD, extracellular vesicles, senolytics, and drug delivery. Novel approaches encompassing unique EV sources, EV isolation methods, and immunoprofiling technology will enhance knowledge of EV-mediated therapeutic mechanisms in DKD and may advance clinical translation of EVs as novel senotherapeutics, delivery vehicles for senolytics, and/or combination therapies to reduce inflammatory and senescence pathways in diabetic and age-related kidney dysfunction. These novel therapeutics hold potential to alter disease trajectory and extend the healthy lifespan in those with aging DKD.

项目概要 受肥胖和糖尿病困扰的老龄化人口的增加预计将呈指数级增长 糖尿病肾病（DKD）的增长。因此，阻止与衰老相关的肾脏变化的治疗干预措施 必须严格推行 DKD。适应不良炎症会导致 DKD 发病，并且促炎 细胞因子和趋化因子激活巨噬细胞，导致肾脏浸润和肾脏预后不良。然而， 炎症仍然是 DKD 中一个尚未解决的主要损伤途径。我们和其他人证明了 DKD 患者和动物模型中的适应不良炎症与细胞衰老增加有关 和肾功能障碍。因此，通过小分子药物等衰老治疗药物来减少衰老 或细胞衍生成分，可能会阻止 DKD 和与年龄相关的肾脏恶化。因此，当务之急是 需要开发针对多方面发病机制（炎症和细胞 DKD 的衰老），以延长健康寿命。我们和其他人证明间充质基质细胞 (MSC) 通过分泌含有以下物质的细胞外囊泡 (EV) 来抑制炎症反应 生物活性物质，主要是 microRNA (miRNA)，并减少衰老负担并延长寿命 老化小鼠模型。尽管 MSC-EV 的治疗活性先前已在衰老和 炎症性疾病模型，这些生物治疗药物对炎症和衰老的影响 DKD 仍未被探索。我们的初步结果表明 MSC-EV：（i）减少衰老途径， 小鼠 DKD 中的巨噬细胞浸润和肾损伤，以及 (ii) 可以负载小分子药物来治疗 联合疗法。此外，我们最近的研究首次证明，抗衰老药物达沙替尼 和槲皮素，减少人体衰老细胞丰度并改善衰老细胞引起的肾损伤 小鼠模型中的间隙。我们假设 EVs 具有抗炎和治疗作用 衰老的 DKD，可以通过共同递送 senolytic 药物进一步增强。为了解决这个中心假设， 我们将在体外确定 EV miRNA 对衰老和炎症的影响（目标 1），评估效果 在衰老 DKD 小鼠模型中使用多个来源的 EV（目标 2），并评估 EV 的性能： 达沙替尼和槲皮素的药物输送载体（目标 3）。为了确保本研究的技术成功，我们 组建了一支在衰老、DKD、细胞外囊泡、senolytics 和药物方面具有互补专业知识的团队 送货。涵盖独特 EV 来源、EV 分离方法和免疫分析的新方法 技术将增强对 EV 介导的 DKD 治疗机制的了解，并可能推进临床 将 EV 转化为新型 senotherapy、senolytics 的递送载体和/或联合疗法 减少糖尿病和年龄相关肾功能障碍的炎症和衰老途径。这些小说 治疗方法有可能改变老年 DKD 患者的疾病轨迹并延长其健康寿命。