New Mechanisms in the Pathogenesis of Diabetic Nephropathy

糖尿病肾病发病新机制

• 批准号: 7387319
• 负责人: RAMA NATARAJAN
• 金额: $ 24.84万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7387319
• 关键词: Accounting; Binding; Binding Proteins; Binding Sites; Biochemical Pathway; Biological; Biological Process; Boxing; Cells; Class; Collagen; Complications of Diabetes Mellitus; Condition; Development; Diabetes Mellitus; Diabetic Nephropathy; Diabetic mouse; Dialysis procedure; Disease; Down-Regulation; E-Box Elements; Effectiveness; End stage renal failure; Extracellular Matrix Proteins; Family; Figs - dietary; Foundations; Functional RNA; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Glomerular Mesangial Cell; Healthcare; Kidney; Kidney Diseases; Mediating; MicroRNAs; Molecular; Mus; Nuclear; Pathogenesis; Patients; Physical Dialysis; Play; Proteins; Regulation; Relative (related person); Renal function; Research; Role; Streptozocin; Testing; Therapeutic; Time; Transforming Growth Factor beta; Translations; Work; YY1 Transcription Factor; base; diabetic; feeding; glomerulosclerosis; in vivo; indexing; innovation; insight; loss of function; member; mesangial cell; mouse model; novel; novel therapeutics; promoter; research study; response; sound; therapeutic target; transcription factor; transcriptomics

DESCRIPTION (provided by applicant): Diabetic nephropathy (DN) is one of the major complications of diabetes. It accounts for almost half of all patients with end stage renal disease needing dialysis and is therefore a major health care problem. However the basic underlying molecular mechanisms are not very clear. Transforming growth factor-beta (TGF-¿) has been implicated in the pathogenesis of DN. It is induced under diabetic conditions and can increase the expression of extracellular matrix proteins such as collagen in mesangial cells, leading to glomerular dysfunction. In a gene array screen, we identified two new gene targets of TGF-¿ in mesangial cells. One of these was noted to be a key transcription factor that could modulate the expression of collagen. Interestingly, we uncovered a novel connection between this family of transcription factors and two members of a new family of small non-coding RNAs called micro-RNAs (miRs). Recent evidence shows that miRs play important roles in gene regulation since they can suppress translation of target genes by binding to their mRNAs. Although several targets of miRs have been predicted, much needs to be done to determine their biological and disease relevance. Furthermore, nothing is known in the context of diabetic complications including DN and we propose to explore our innovative idea in this context. We discovered that our newly identified transcription factor targets of TGF-¿ that are involved in collagen regulation, are also targets of two miRs that are expressed in the kidney. Furthermore, interestingly, these transcription factors in turn can inhibit the expression of these miRs, thereby suggesting a novel cross talk and feed forward loop that can contribute to mesangial cell and glomerular matrix expression. We therefore put forward the innovative hypothesis that DN is a result of aberrant expression and actions of these miRs in the kidney and mesangial cells in response to TGF-¿. Specific Aims 1 and 2 will examine gain and loss of function approaches as well as transcriptomic mechanisms to evaluate the involvement of the new TGF-¿ targets and two miRs in mouse mesangial cell gene expression. Specific Aim 3 will then test the in vivo functional relevance in a mouse model of DN by examining the renal cortical expression of miRs and target genes and the effects of downregulation of a key miR. Overall, we will explore new related mechanisms and players in the development of DN. This work could break new ground and have a major impact in the field of renal research as well as lay the foundation for deciphering the biological functions of these elusive factors in the kidney. They could also pave the way for novel new therapies for various complications of diabetes including nephropathy.

描述（由申请人提供）：糖尿病肾病（DN）是糖尿病的主要并发症之一。它几乎占所有需要透析的终末期肾病患者的一半，因此是一个主要的卫生保健问题。然而，其基本的分子机制尚不十分清楚。转化生长因子-β（TGF-β）与DN的发病机制有关。它在糖尿病条件下被诱导，并且可以增加系膜细胞中细胞外基质蛋白如胶原蛋白的表达，导致肾小球功能障碍。在基因阵列筛选中，我们在系膜细胞中鉴定了TGF-β的两个新基因靶点。其中之一被认为是一个关键的转录因子，可以调节胶原蛋白的表达。有趣的是，我们发现了这个转录因子家族与称为micro-RNAs（miRs）的小非编码RNA新家族的两个成员之间的新联系。最近的证据表明，miR在基因调控中起着重要作用，因为它们可以通过与靶基因的mRNA结合来抑制靶基因的翻译。尽管已经预测了miR的几个靶点，但仍需要做很多工作来确定其生物学和疾病相关性。此外，在糖尿病并发症（包括DN）的背景下，我们一无所知，我们建议在此背景下探索我们的创新想法。我们发现，我们新鉴定的TGF-β的转录因子靶点参与胶原调节，也是肾脏中表达的两种miR的靶点。此外，有趣的是，这些转录因子反过来可以抑制这些miR的表达，从而表明一种新的串扰和前馈环，可以有助于系膜细胞和肾小球基质表达。因此，我们提出了创新的假设，即DN是这些miR在肾脏和系膜细胞中响应TGF-β的异常表达和作用的结果。具体目标1和2将检查功能获得和丧失的方法以及转录组学机制，以评估新的TGF-β靶点和两种miR在小鼠系膜细胞基因表达中的参与。特异性目的3然后将通过检查miR和靶基因的肾皮质表达以及关键miR的下调的影响来测试DN小鼠模型中的体内功能相关性。总的来说，我们将探索DN发展中新的相关机制和参与者。这项工作可能会开辟新天地，并在肾脏研究领域产生重大影响，并为破译肾脏中这些难以捉摸的因子的生物学功能奠定基础。它们还可以为糖尿病各种并发症（包括肾病）的新疗法铺平道路。