A new pathogenic mechanism for diabetic retinopathy

描述(申请人提供)：越来越多的证据表明，糖尿病视网膜病变(DR)是一种慢性炎症性疾病。在之前的资助期间，我们已经成功地证实了在DR的视网膜炎症和新生血管(NV)中，典型的Wnt通路的异常激活在视网膜炎症和新生血管(NV)中起着关键的致病作用。本项目代表了我们先前研究的合理扩展，旨在阐明在DR中Wnt通路过度激活的机制。PPAR是一种激素激活的受体和转录因子。两项独立的临床研究报告了令人惊讶的发现，口服非诺贝特，一种小分子PPAR激动剂，对2型糖尿病患者的DR具有强大的治疗效果。然而，这种对DR有益的作用机制尚不清楚，PPAR在视网膜中的功能也不清楚。最近，我们发现PPAR？与DR有关：1)PPAR？在视网膜中表达。2)PPAR？在1型和2型糖尿病模型视网膜中的表达均下调。3)非诺贝特可减轻糖尿病视网膜病变模型的视网膜炎症和血管渗漏。4)非诺贝特抑制Wnt信号转导，下调糖尿病及Wnt配体诱导的Wnt靶基因表达。5)单独过表达PPAR可抑制Wnt信号转导。6)PPAR基因敲除(KO)可阻断非诺贝特对糖尿病视网膜血管渗漏的影响。基于这些结果，我们假设PPAR？抑制视网膜中的WNT信号和炎症，并且糖尿病视网膜中PPAR？的表达减少在DR中起重要的致病作用。我们建议进行以下研究：1)我们将首先确定糖尿病导致的PPAR？下调在DR视网膜炎症和血管渗漏中的作用。我们将在PPAR？-/-小鼠中诱导糖尿病，并确定PPAR？？KO是否会加剧Dr.糖尿病。PPAR？/-小鼠将接受非诺贝特治疗，以确定是否缺乏PPAR？可以取消非诺贝特对Dr.的治疗作用。我们还将确定PPAR？在糖尿病大鼠视网膜中的过度表达是否改善Dr.2)我们将检验PPAR？在糖尿病视网膜中的表达减少与视网膜中Wnt信号的异常激活有关的假设。具体地说，我们将调查PPAR？KO是否会加剧糖尿病诱导的视网膜中Wnt通路的激活。我们还将阐明PPAR下调Wnt途径的机制。3)我们将明确糖尿病导致视网膜中PPAR下调的机制。这些研究将定义PPAR和Wnt信号之间的新的相互作用，建立DR视网膜炎症的新的致病机制，并确定Wnt信号的内源性调节因子。这些研究还将阐明非诺贝特治疗糖尿病视网膜病变的机制，并确定治疗的新药靶点。

DESCRIPTION (provided by applicant): Accumulating evidence suggest that diabetic retinopathy (DR) is a chronic inflammatory disorder. In the prior grant period, we have successfully established that aberrant activation of the canonical Wnt pathway in the retina plays a key pathogenic role in retinal inflammation and neovascularization (NV) in DR. This project represents a logical extension of our previous studies and aims to elucidate the mechanism responsible for the Wnt pathway over-activation in DR. Peroxisome proliferator-activated receptor-¿ (PPAR¿) is a hormone-activated receptor and transcription factor. Two independent clinical studies reported surprise findings that oral administration of fenofibrate, a small molecule PPAR¿ agonist, confers robust therapeutic effects on DR in type 2 diabetic patients. However, the mechanism for this beneficial effect on DR has not been elucidated, and the function of PPAR¿ in the retina is unknown. Recently, we have the following finding implicating PPAR¿ in DR: 1) PPAR¿ is expressed in the retina. 2) PPAR¿ expression is down-regulated in the retinas of both type 1 and type 2 diabetic models. 3) Fenofibrate ameliorates retinal inflammation and vascular leakage in DR models. 4) Fenofibrate inhibits Wnt signaling and down-regulates Wnt target genes induced by diabetes and by Wnt ligands. 5) Over-expression of PPAR¿ alone suppressed Wnt signaling. 6) PPAR¿ knockout (KO) abolishes the effects of fenofibrate on diabetes-induced retinal vascular leakage. Based on these results, we hypothesize that PPAR¿ inhibits Wnt signaling and inflammation in the retina, and that the decreased PPAR¿ expression in the diabetic retina plays an important pathogenic role in DR. To test this hypothesis, we propose the following studies: 1) We will first establish the role of diabetes-induced down-regulation of PPAR¿ in retinal inflammation and vascular leakage in DR. We will induce diabetes in PPAR¿-/- mice and determine if PPAR¿ KO exacerbates DR. Diabetic PPAR¿-/- mice will be treated with fenofibrate to determine if lack of PPAR¿ abolishes the therapeutic effect of fenofibrate on DR. We will also determine if over-expression of PPAR¿ in the retina of diabetic rats ameliorates DR. 2) We will test the hypothesis that decreased PPAR¿ expression in diabetic retina is responsible for the aberrant activation of Wnt signaling in the retina. Specifically, we will investigate if PPAR¿ KO exacerbates the diabetes-induced Wnt pathway activation in the retina. We will also elucidate the mechanism by which PPAR¿ down-regulates the Wnt pathway. 3) We will define the mechanism responsible for diabetes-induced down- regulation of PPAR¿ in the retina. These studies will define novel interactions between PPAR¿ and Wnt signaling, establish a novel pathogenic mechanism for retinal inflammation in DR and identify an endogenous regulator of Wnt signaling. These studies will also elucidate the mechanism for the fenofibrate's effects on DR and identify a new drug target for the treatment.