Autophagy in Diabetic Kidney Disease

项目摘要/摘要 糖尿病肾病(DKD)在临床和机制上具有异质性。在场的个别患者患有 估计的肾小球滤过率(EGFR)和蛋白尿的变化轨迹可能不一致 肾脏组织病理损伤的严重程度，反映长期结果，或预测对 心理治疗。阐明DKD发病的分子机制可能有助于解释 DKD的临床表现，并允许实施新的个性化诊断、预后和 治疗策略。自噬，细胞质成分，如受损细胞器的过程 被运送到溶酶体并被降解，是维持肾脏细胞内平衡所必需的 是一种很有前途的评估DKD的机制。虽然肾脏自噬已经在 在实验性糖尿病模型中，自噬在人类DKD中的作用仍然是一个主要的知识空白。 该项目的总体目标是全面描述人类DKD的自噬现象。 利用临床、组织病理学和分子表型，为机械性- 有针对性的诊断和治疗战略。该项目将利用肾脏分子、临床和 来自肾脏精准医学项目(KPMP)的组织病理学数据，一种纵向的2型糖尿病猪 印度队列和华盛顿大学(UW)肾脏活检队列。在目标1中，我将定义临床， KPMP中DKD自噬的分子和组织病理学模式。具体地说，我将比较 肾组织自噬的标记物(通过电子显微镜评估自噬小体数量，自噬- 相关基因表达、自噬相关蛋白浓度)。我 还将调查肾脏自噬标记物与临床和组织病理学特征的关系。在……里面 目的2，我将测试肾脏自噬标志物与测量的GFR和 皮马印第安人队列中的蛋白尿。在目标3中，我将开发尿液和血液生物标记物签名，开发 并在KPMP中进行内部验证，在皮马印第安人和UW队列中进行外部验证。 我的目标是成为一名内科科学家，专注于DKD和精确医学的研究。至 完成我的研究和职业发展目标，我设计了一个由团队支持的培训计划 由具有DKD、生物信息学、流行病学和肾脏组织病理学专业知识的导师和合作者组成。 该项目将对DKD中的自噬以及尿液和血液中的生物标志物签名产生新的见解 评估肾组织自噬，可应用于其他队列。更好地理解 DKD的自噬可能为具有不同预后和反应的基于分子的亚群铺平道路 现有的和新的治疗方法。

PROJECT SUMMARY/ABSTRACT Diabetic kidney disease (DKD) is clinically and mechanistically heterogeneous. Individual patients present with variable trajectories of estimated glomerular filtration rate (eGFR) and albuminuria that may not be concordant with severity of kidney histopathological injury, reflective of long-term outcomes, or predictive of response to therapy. Elucidating the molecular mechanisms underlying DKD pathogenesis may help explain differences in DKD’s clinical presentation and allow implementation of novel personalized diagnostic, prognostic, and therapeutic strategies. Autophagy, the process by which cytoplasmic components such as damaged organelles are delivered to lysosomes and degraded, is essential for maintenance of cellular homeostasis in the kidney and is a promising mechanism to evaluate in DKD. While kidney autophagy has been studied in extensively in experimental diabetes models, the role of autophagy in human DKD remains a major knowledge gap. The overall goal of the project proposed here is to comprehensively characterize autophagy in human DKD using clinical, histopathological, and molecular phenotyping, establishing a foundation for mechanistically- targeted diagnostic and therapeutic strategies. This project will leverage kidney molecular, clinical, and histopathologic data from the Kidney Precision Medicine Project (KPMP), a longitudinal type 2 diabetes Pima Indian cohort, and a University of Washington (UW) kidney biopsy cohort. In Aim 1, I will define clinical, molecular, and histopathological patterns of autophagy in DKD in the KPMP. Specifically, I will compare markers of autophagy in kidney tissue (autophagosome number assessed via electron microscopy, autophagy- related gene expression, autophagy-related protein concentrations) between adults with DKD and controls. I will also investigate associations of kidney autophagy markers with clinical and histopathological features. In Aim 2, I will test associations of kidney autophagy markers with long-term changes in measured GFR and albuminuria in the Pima Indian cohort. In Aim 3, I will develop urine and blood biomarker signatures, developed and internally validated in the KPMP and externally validated in the Pima Indian and UW cohorts. I aim to establish a career as a physician-scientist with a research focus on DKD and precision medicine. To accomplish my research and career development goals, I have designed a training plan supported by a team of mentors and collaborators with expertise in DKD, bioinformatics, epidemiology, and kidney histopathology. This project will generate novel insights into autophagy in DKD and urine and blood biomarker signatures for assessing kidney tissue autophagy which can be applied to other cohorts. Improved understanding of autophagy in DKD may pave the way for molecular-based subgroups with distinct prognoses and responses to existing and novel therapies.