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The Role of Aminopeptidase-A in GBM Thickening in Diabetic Nephropathy

氨肽酶-A 在糖尿病肾病 GBM 增厚中的作用

基本信息

批准号：
9378083
负责人：
Caroline B Marshall
金额：
--
依托单位：
BIRMINGHAM VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-10-01 至 2018-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9378083
关键词：
Address Affect Albuminuria Applications Grants Award BALB/cJ Mouse Binding Biological Breeding Cell Nucleus Chronic Kidney Failure Clinical Communication Culture Media Cytoplasmic Tail Development Development Plans Diabetes Mellitus Diabetic Nephropathy Disease Dissociation Down-Regulation End stage renal failure Epithelial Cells Expression Profiling Extracellular Matrix Family Funding Gene Expression Gene Targeting Genes Glucose Goals Grant Harvest Heterodimerization Human Hyperglycemia Image In Vitro Injury Insulin Insulin Receptor Integral Membrane Protein Kidney Knock-out Knockout Mice Laboratories Link Manuscripts Measurement Mediating Mentors Messenger RNA Modeling Molecular Morphology Mus Nuclear Nuclear Localization Signal Nuclear Translocation Pathogenesis Pathway interactions Patients Phenotype Play Population Prevalence Proteins Publishing Rattus Receptor Down-Regulation Receptor Signaling Regulation Renin-Angiotensin System Reporting Research Role Schedule Small Interfering RNA Streptozocin Testing Thick TimeLine Training United States United States National Institutes of Health Western Blotting Work Writing Zinc Fingers base career development clinical care db/db mouse design diabetic diabetic patient diabetic rat expectation glomerular basement membrane glutamyl aminopeptidase improved in vivo knock-down meetings member migration overexpression patient population podocyte protein protein interaction public health relevance skills targeted treatment transcription factor type I diabetic

项目摘要

DESCRIPTION (provided by applicant): PROJECT SUMMARY Diabetes mellitus is the most common cause of chronic kidney disease. Approximately 40% of diabetic patients develop diabetic nephropathy (DN); and nearly half of all incident cases of end-stage renal disease in the United States are due to DN. Despite widespread use of targeted therapies to lower glucose and to antagonize the renin-angiotensin system, the prevalence of DN has remained stable. Thus, effective and disease-specific therapies for DN are needed. The immediate goal of the applicant is to study the mechanisms underlying the development of glomerular basement membrane (GBM) thickening in DN. The applicant's long- term goal is to understand the pathogenesis of diabetic kidney disease in sufficient detail to develop mechanism-based therapies for DN. A clear and focused career development plan has been designed by the applicant and the mentoring team to provide new and enhanced training in cell-extracellular matrix interactions in DN, insulin receptor signaling, communication and presentation skills, grant and manuscript writing, and responsible conduct in research. There is a plan for progressive increase in independence over the course of the CDA-2 Award. Timelines for the specific aims, laboratory space allocation, scheduled meetings between the applicant and the mentoring team, expectations of the applicant, and the specific role(s) of each mentor are addressed in detail in the career development plan. In addition, the applicant is expected to submit smaller grant proposals in the earlier years and an application for independent funding (VA Merit Award, NIH R01) in the last two years of the CDA-2 Award. Studies currently being conducted by the applicant have demonstrated that aminopeptidase-A (APA), a type II transmembrane protein expressed in visceral glomerular epithelial cells (podocytes), may play an important role in the pathogenesis of GBM thickening in DN. Initial results show that APA knockout mice have significantly thickened GBMs. Moreover, APA is down-regulated in patients with DN and in rat models of type 2 DN. Also, knockdown of the insulin receptor in cultured glomerular epithelial cells reduces the expression of APA. In this proposal, the applicant will study the role of APA downregulation in mediating the expression of genes involved in GBM remodeling. The overall hypothesis is that APA down-regulation in the diabetic state causes displacement of transcriptional factors (ZHX proteins) that migrate into the podocyte nucleus and induce changes in the expression of matrix- related genes, thereby leading to GBM thickening. The goal of the proposed studies is to increase our understanding of key molecular changes that result in the development of GBM thickening and DN. In Specific Aim 1, the effects of APA down-regulation on matrix-related gene expression will be studied. In Specific Aim 2, the importance of APA-ZHX interaction in the development of GBM thickening will be examined. In Specific Aim 3, the effects of insulin receptor deficiency on APA and ZHX proteins will be investigated.

描述（由申请人提供）：糖尿病是慢性肾脏病最常见的病因。大约40%的糖尿病患者发展为糖尿病肾病（DN）;在美国，近一半的终末期肾病病例是由于DN。尽管广泛使用靶向治疗来降低血糖和拮抗肾素-血管紧张素系统，但DN的患病率仍保持稳定。因此，需要针对DN的有效和疾病特异性的治疗。申请人的近期目标是研究DN中肾小球基底膜（GBM）增厚发展的潜在机制。申请人的长期目标是充分详细地了解糖尿病肾病的发病机制，以开发基于机制的DN疗法。申请人和指导团队设计了一个明确而有重点的职业发展计划，以提供DN细胞-细胞外基质相互作用，胰岛素受体信号传导，沟通和演讲技巧，赠款和手稿写作以及负责任的研究行为方面的新的和增强的培训。有一项计划是在CDA-2裁决期间逐步提高独立性。具体目标的时间表，实验室空间分配，申请人和指导团队之间的预定会议，申请人的期望，以及每个导师的具体角色在职业发展计划中详细说明。此外，申请人预计将提交较小的赠款建议在早些年和申请独立的资金（VA优异奖，NIH R 01）在CDA-2奖的最后两年。申请人目前正在进行的研究已经证明，氨肽酶-A（阿帕），一种在内脏肾小球上皮细胞（足细胞）中表达的II型跨膜蛋白，可能在DN中GBM增厚的发病机制中起重要作用。初步结果显示阿帕敲除小鼠具有显著增厚的GBM。此外，阿帕在DN患者和2型DN大鼠模型中下调。此外，在培养的肾小球上皮细胞中，胰岛素受体的敲低降低了阿帕的表达。在该提案中，申请人将研究阿帕下调在介导参与GBM重塑的基因表达中的作用。总体假设是，糖尿病状态下阿帕下调导致迁移到足细胞核中的转录因子（ZHX蛋白）的置换，并诱导基质相关基因表达的变化，从而导致GBM增厚。这些研究的目的是增加我们对导致GBM增厚和DN发展的关键分子变化的理解。在具体目标1中，将研究阿帕下调对基质相关基因表达的影响。在具体目标2中，将检查APA-ZHX相互作用在GBM增厚发展中的重要性。在具体目标3中，将研究胰岛素受体缺乏对阿帕和ZHX蛋白的影响。