Autophagy in Diabetic Kidney Disease

糖尿病肾病中的自噬

• 批准号: 10642559
• 负责人: Christine Limonte
• 金额: $ 18.91万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10642559
• 关键词: Adult; Advanced Glycosylation End Products; Affect; Agonist; Albumins; Albuminuria; Autophagocytosis; Autophagosome; Bioinformatics; Blood; Cathepsins; Chronic Kidney Failure; Clinical; Clinical Trials; Cohort Studies; Cytoplasm; Data; Diabetes Mellitus; Diabetic Nephropathy; Diagnosis; Diagnostic; Disease model; Electron Microscopy; End stage renal failure; Enrollment; Enzymes; Epidemiology; Epithelial Cells; Excretory function; Experimental Diabetes Mellitus; Experimental Models; Fellowship; Fibrosis; Foundations; Future; GLP-I receptor; Gene Expression; Genes; Glomerular Filtration Rate; Glucose; Goals; Heterogeneity; Histopathology; Homeostasis; Human; Hyperglycemia; Hypoxia; Immunohistochemistry; Inflammation; Injury; Injury to Kidney; Investigation; Kidney; Knowledge; LCN2 gene; Laboratories; Longitudinal cohort; Lysosomes; Maintenance; Measures; Mediating; Mentors; Methodology; Modeling; Molecular; Morbidity - disease rate; Mus; Non-Insulin-Dependent Diabetes Mellitus; Organelles; Outcome; Oxidative Stress; Participant; Pathogenesis; Pathway interactions; Pattern; Persons; Physicians; Pima Indian; Plasma; Play; Prediction of Response to Therapy; Predisposition; Process; Prognosis; Proteins; Proteomics; Renal function; Research; Research Project Grants; Role; Scientist; Severities; Sodium; Subgroup; Testing; Therapeutic; Tissues; Training; Tubular formation; Universities; Urine; Washington; Work; biomarker signature; career; career development; cell injury; cohort; design; detection of nutrient; diabetic; disorder subtype; experience; hypertensive; improved; individual patient; inhibitor; insight; kidney biopsy; light microscopy; molecular phenotype; mortality; novel; novel therapeutic intervention; novel therapeutics; personalized diagnostics; personalized therapeutic; precision medicine; prognostic; research and development; response; severe injury; symporter

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.

项目概要/摘要 糖尿病肾病（DKD）在临床和机制上具有异质性。 估计肾小球滤过率 (eGFR) 和蛋白尿的变化轨迹可能不一致 与肾脏组织病理学损伤的严重程度、反映长期结果或预测反应 阐明 DKD 发病机制的分子机制可能有助于解释 DKD 的差异。 DKD 的临床表现并允许实施新颖的个性化诊断、预后和治疗 自噬，细胞质成分（例如受损的细胞器）的过程。 被递送至溶酶体并降解，对于维持肾脏细胞稳态至关重要 肾自噬是一种很有前景的 DKD 评估机制。 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。 这里提出的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分析，为机制奠定了基础 该项目将利用肾脏分子、临床和治疗策略。 来自肾脏精准医学项目 (KPMP) 的组织病理学数据，纵向 2 型糖尿病 Pima 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、 具体来说，我将比较 KPMP 中 DKD 自噬的分子和组织病理学模式。 肾组织中自噬的标志物（通过电子显微镜评估自噬体数量，自噬- DKD 成人和对照 I 之间的相关基因表达、自噬相关蛋白浓度。 还将研究肾脏自噬标记物与临床和组织病理学特征的关联。 目标 2，我将测试肾脏自噬标记物与测量的 GFR 和 GFR 的长期变化之间的关联 在目标 3 中，我将开发尿液和血液生物标志物特征。 并在 KPMP 中进行内部验证，并在皮马印第安人和华盛顿大学队列中进行外部验证。 我的目标是成为一名医师科学家，重点研究 DKD 和精准医学。 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生物标志物特征产生新的见解。 评估肾组织自噬，可应用于其他群体。 DKD 中的自噬可能为基于分子的亚组铺平道路，这些亚组具有不同的预后和反应 现有的和新颖的疗法。