A new pathogenic mechanism for diabetic retinopathy

描述（由申请人提供）：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。在之前的资助期内，我们已经成功地确定了视网膜中典型Wnt通路的异常激活在dr视网膜炎症和新生血管（NV）中起关键的致病作用。该项目是我们之前研究的逻辑延伸，旨在阐明dr中Wnt通路过度激活的机制。过氧化物酶体增殖体激活受体-¿（PPAR¿）是一种激素激活受体和转录因子。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有益作用的机制尚未阐明，PPAR¿在视网膜中的功能尚不清楚。最近，我们有以下发现提示PPAR¿在DR中：1)PPAR¿在视网膜中表达。2) 1型和2型糖尿病模型视网膜中PPAR¿表达均下调。3)非诺贝特改善DR模型视网膜炎症和血管渗漏。4)非诺贝特抑制糖尿病及Wnt配体诱导的Wnt信号通路，下调Wnt靶基因。5) PPAR¿单独过表达抑制Wnt信号。6) PPAR基因敲除（KO）可消除非诺贝特对糖尿病性视网膜血管渗漏的影响。基于这些结果，我们假设PPAR¿抑制Wnt信号和视网膜炎症，并且PPAR¿在糖尿病视网膜中表达降低在dr中起重要的致病作用。为了验证这一假设，我们提出以下研究：1)我们将首先建立的角色diabetes-induced下调视网膜炎症和血管渗漏的害怕PPAR害怕我们会诱发糖尿病博士在PPAR - / -小鼠和确定害怕PPAR KO加剧糖尿病害怕PPAR - / -小鼠博士将与非诺贝特治疗来确定缺乏PPAR博士,害怕破坏的非诺贝特治疗效果我们还将确定害怕PPAR在糖尿病大鼠视网膜的表达改善博士2)我们将测试假设降低了糖尿病视网膜中PPAR¿的表达是导致视网膜中Wnt信号异常激活的原因。具体来说，我们将研究PPAR¿KO是否会加剧糖尿病诱导的视网膜Wnt通路激活。我们还将阐明PPAR¿下调Wnt通路的机制。3)我们将明确糖尿病诱导视网膜中PPAR¿下调的机制。这些研究将定义PPAR¿和Wnt信号之间的新相互作用，建立DR视网膜炎症的新致病机制，并确定Wnt信号的内源性调节因子。这些研究也将阐明非诺贝特对DR的作用机制，并确定治疗的新药物靶点。

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.