Causal connections between axon guidance proteins and early progressive kidney function decline in diabetes

轴突引导蛋白与糖尿病早期进行性肾功能衰退之间的因果关系

• 批准号: 10343592
• 负责人: Andrzej S Krolewski
• 金额: $ 76.97万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10343592
• 关键词: Affect; Clinical; Cohort Studies; Collaborations; Data; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Disease; EPHA2 gene; EPHB2 gene; End stage renal failure; EphA2 Receptor; Etiology; Genetic study; Human; Impairment; Incidence; Insulin-Dependent Diabetes Mellitus; Kidney; Kidney Diseases; Lead; Learning; Lesion; Ligands; Link; Methods; MicroRNAs; Molecular; Mus; Nested Case-Control Study; Non-Insulin-Dependent Diabetes Mellitus; Observational Study; Orthologous Gene; Pathway interactions; Patients; Phenotype; Pima Indian; Plasma; Prevention; Probability; Process; Prognostic Marker; Protective Agents; Proteins; Proteinuria; Renal function; Research; Research Personnel; Resources; Risk; Role; Specimen; Technology; Testing; The Jackson Laboratory; United States; Variant; axon guidance; biobank; circulating microRNA; cohort; diabetic patient; follow-up; functional decline; genetic manipulation; glycemic control; kidney biopsy; kidney cell; member; mouse genetics; mouse model; multidisciplinary; non-diabetic; novel; renal damage; single-cell RNA sequencing; success; therapeutic target

PROJECT SUMMARY/ABSTRACT End stage kidney disease (ESKD) due to diabetes continues to rise despite improvements in glycemic control and widespread treatment with reno-protective drugs. A more complete understanding of the mechanisms responsible for the progressive decline in kidney function is urgently needed to identify new, more efficacious methods of treatment and prevention of ESKD in diabetes. By studying diabetic patients with advanced kidney disease with proteinuria and CKD≥3, we obtained two novel findings related to progression to ESKD in both T1D and T2D. Using follow-up data from two independent cohorts and global miRNAs platform, we found a specific profile of plasma miRNAs strongly associated with progression to ESKD. These miRNAs specifically targeted axon guidance pathway (AGP) proteins. Strikingly, circulating levels of 6 AGP proteins (two ligands EFNA4, EFN5 and 4 receptors EPHA2, EPHB2, EPHB6, UNC5C) were very strongly associated with the extent of kidney structural lesions in the T2D Pima Indian cohort and progression to ESKD in four independent cohorts. Our findings are the first to implicate circulating AGP proteins in the progression to ESKD in diabetes. To follow-up these findings, we propose a multi-disciplinary study to assess the role of the AGP proteins in the development of early progressive kidney functional decline (PKFD) and learn about mechanisms through which circulating AGP may damage the kidney. Three complementary studies are proposed. Dr. Krolewski’s lab will examine whether elevated levels of two exemplars of AGP proteins EFNA4 and EPHA2 are associated/causally related to the development of early PKFD. Dr. Kretzler’s lab will examine how circulating levels of the AGP proteins may impact candidate etiological pathways in kidney cells. Dr. Korstanje’s lab will examine whether genetic manipulation of circulating levels of EFNA4 and EPHA2 in mice models of diabetes lead to onset of diabetic kidney disease. The proposed research has the following specific aims: Aim #1: We will examine the effect of variation of circulating levels of the candidate miRNAs and AGP proteins examined at baseline in the two nested cases-control studies of T1D patients with Normo-Alb (n=390) and Micro- Alb (n=430) on risk of early PKFD during 7-15 years of follow-up. Aim #2: We will examine the link between circulating levels of the candidate AGP proteins and dysregulation of candidate etiological pathways using single cell RNA sequencing results obtained from research kidney biopsies from Pima Indians with T2D. Aim #3: We will test EPHA2 and EFNA4 for their ability to modify renal phenotypes in a diabetic mouse model and test whether miR-328-5p and miR-339-5p, which are both downregulated during progression to ESKD and have orthologs in the mouse, can affect the impact of these AGP proteins on diabetic kidney disease. The proposed research has a very high probability of generating novel findings. Its success is assured by the fact that the co-investigators have a track record of collaboration, and study cohorts and biobanks of specimens from all members of the Joslin Kidney Study and Pima Indian Kidney Study are available.

项目概要/摘要 尽管血糖控制有所改善，但糖尿病引起的终末期肾病 (ESKD) 仍在继续上升 以及肾脏保护药物的广泛治疗。对其机制有更全面的了解。 迫切需要找出新的、更有效的治疗方法来解释导致肾功能逐渐下降的原因 通过研究患有晚期肾病的糖尿病患者来治疗和预防糖尿病中的ESKD。 患有蛋白尿且 CKD≥3 的疾病，我们获得了两项与 T1D 进展为 ESKD 相关的新发现 使用来自两个独立队列和全球 miRNA 平台的后续数据，我们发现了一个特定的。 血浆 miRNA 的谱与 ESKD 的进展密切相关，这些 miRNA 是专门针对的。 引人注目的是，6 种 AGP 蛋白（两种配体 EFNA4、 EFN5 和 4 受体 EPHA2、EPHB2、EPHB6、UNC5C) 与肾脏的程度密切相关 T2D Pima Indian 队列的结构性病变以及四个独立队列进展为 ESKD。 研究结果首次表明循环 AGP 蛋白与糖尿病 ESKD 的进展有关。 为了跟进这些发现，我们提出了一项多学科研究来评估 AGP 蛋白在 早期进行性肾功能衰退 (PKFD) 的发展并了解其机制 Krolewski 博士的实验室将提出三项补充研究。 检查 AGP 蛋白 EFNA4 和 EPHA2 的两个示例的水平升高是否相关/因果关系 与早期 PKFD 的发展相关。Kretzler 博士的实验室将检查 AGP 的循环水平。 蛋白质可能会影响肾细胞中的候选病因学途径。Korstanje 博士的实验室将检查是否存在这种情况。 对糖尿病小鼠模型中 EFNA4 和 EPHA2 循环水平进行基因操作会导致糖尿病的发生 拟议的研究有以下具体目标： 目标#1：我们将检查候选 miRNA 和 AGP 蛋白循环水平变化的影响 在对 T1D 患者进行的两项巢式病例对照研究中，在基线时对 Normo-Alb (n=390) 和 Micro-Alb 进行了检查。 Alb (n=430) 在 7-15 年的随访期间发生早期 PKFD 的风险。目标 #2：我们将检查之间的联系。 候选 AGP 蛋白的循环水平和候选病因学途径的失调 从患有 T2D 的皮马印第安人的研究肾活检中获得的细胞 RNA 测序结果：我们。 将测试 EPHA2 和 EFNA4 在糖尿病小鼠模型中改变肾脏表型的能力，并测试 miR-328-5p 和 miR-339-5p 是否在 ESKD 进展过程中均被下调，并且 小鼠中的直系同源物可以影响这些 AGP 蛋白对糖尿病肾病的影响。 所提出的研究很有可能产生新颖的发现，其成功是由以下因素保证的。 事实上，共同研究人员有合作记录，研究队列和样本生物库 来自 Joslin 肾脏研究和 Pima 印度肾脏研究所有成员的信息均可获取。