Autophagy in Diabetic Kidney Disease

项目总结/摘要 糖尿病肾病（DKD）的临床和机制是异质性的。个体患者存在 估计肾小球滤过率（eGFR）和蛋白尿的变化轨迹可能不一致 肾组织病理学损伤的严重程度，反映长期结局，或预测对 疗法阐明DKD发病机制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， 治疗策略自噬，细胞质成分如受损细胞器 被递送到溶酶体并降解，对于维持肾脏中的细胞稳态是必需的 并且是在DKD中评估的有前途的机制。虽然肾脏自噬已经在许多领域得到了广泛的研究， 尽管在实验糖尿病模型中，自噬在人类DKD中的作用仍然是一个主要的知识缺口。 该项目的总体目标是全面表征人类DKD中的自噬 利用临床、组织病理学和分子表型，建立一个机制上的基础， 有针对性的诊断和治疗策略。该项目将利用肾脏分子，临床和 肾脏精准医学项目（KPMP）的组织病理学数据，一项纵向2型糖尿病Pima研究， 印度队列和华盛顿大学（UW）肾活检队列。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。具体来说，我将比较 肾组织中自噬的标志物（通过电子显微镜评估的自噬体数目，自噬- 相关基因表达，自噬相关蛋白浓度）。我 还将研究肾脏自噬标记物与临床和组织病理学特征的关系。在 目的2，我将测试肾脏自噬标记物与GFR测量值的长期变化之间的关系， 在皮马印第安人队列中发现蛋白尿。在目标3中，我将开发尿液和血液生物标志物签名， 并在KPMP中进行了内部验证，在Pima Indian和UW队列中进行了外部验证。 我的目标是建立一个职业生涯作为一个医生，科学家与DKD和精准医学的研究重点。到 为了实现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， 在DKD，生物信息学，流行病学和肾脏组织病理学方面具有专业知识的导师和合作者。 该项目将对DKD中的自噬以及尿液和血液生物标志物特征产生新的见解， 评估肾组织自噬，其可以应用于其他群组。更好地了解 DKD中的自噬可能为基于分子的亚群铺平道路，这些亚群具有不同的凋亡和对 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.