Molecular Signaling in Cataracts

白内障的分子信号传导

基本信息

批准号：
10188536
负责人：
Jonathan Mark Petrash
金额：
$ 37.71万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188536
关键词：
Adaptor Signaling Protein Address Adopted Aldehyde Reductase Aluminum Animal Model Attenuated Binding Blindness Caregivers Cataract Cataract Extraction Cell Membrane Permeability Cells Clinical Combined Modality Therapy Complex Development Docking Drug Targeting Epithelial Epithelial Cells Excision Extracapsular Eye Eye diseases Fibroblasts Financial Hardship Genes Genetic Transcription Growth Factor Interruption Knockout Mice Lasers Lead Light Link Measures Mediating Mediator of activation protein Medical Mesenchymal Modeling Molecular Morphology Mus Operative Surgical Procedures Pathogenesis Pathogenicity Patients Pharmacologic Substance Pharmacology Phenotype Physiologic Intraocular Pressure Prevalence Prevention Prevention strategy Procedures Process Proliferating Proteins Quality of life Reporting Retinal Detachment Retinal Edemas Risk Signal Transduction Signaling Protein Smad Proteins Smooth Muscle Actin Staining Method Structure Surgical complication Testing Therapeutic Therapeutic Agents Thinness Time Transforming Growth Factor beta Transforming Growth Factor beta Receptors Transgenic Mice Transitional Epithelium Visual Acuity Work World Health Organization Yttrium arm blind capsule cell behavior comparative cytokine design diabetic diabetic cataract enzyme pathway epithelial to mesenchymal transition fiber cell global health high risk inhibitor/antagonist lens mouse model mutant polyol prevent protein biomarkers receptor recruit response synergism therapeutically effective wound response

项目摘要

Project Summary Cataract is one of the major causes of blindness worldwide. Following surgical removal of the cataractous lens, approximately 20% of cataract patients develop posterior capsular opacification (PCO) and significantly compromised quality of life. Given the prevalence of cataract and the relatively high rate of PCO following cataract surgery, especially among young patients who develop a more aggressive PCO as well as the increasing number of diabetics at higher risk to develop PCO, there is an urgent need for therapies to prevent cellular changes that lead to this blinding condition. There is currently no medical therapy to effectively prevent PCO and no alternative to capsulotomy for its treatment. Thus, the long-term impact of this work will address a currently unmet clinical need—the prevention of PCO using pharmaceutical agents to suppress growth factor signaling responsible for PCO development. Transforming growth factor-beta (TGF-β) is recognized as one of the major growth factors that drive PCO pathogenesis. TGF-β induces activation of Smad proteins, which then bring about transcription of a battery of genes involved in the shift of epithelial cells to a mesenchymal phenotype, known as epithelial-to-mesenchymal transition (EMT). In preliminary studies we showed that aldose reductase (AR), a polyol pathway enzyme linked to diabetic eye disease, facilitates Smad activation by TGF-β. Proposed studies seek to devise therapeutic strategies to interrupt the pathogenic signals that drive the PCO process. In Aim 1, we will use transgenic mouse models as a platform to test the hypothesis that AR facilitates EMT in PCO pathogensis. Comparative risk for PCO development will be measured in our AR-Tg mice, AR null mice (ARKO), and wild type C57BL6 mice, using immunostaining and quantitative PCR to measure EMT and structural markers in the lens at various times following surgery. In Aim 2, we will decipher the mechanism linking AR to TGFß-mediated signaling in PCO development. We will utilize mutant forms of AR and TGFß-receptor adaptor proteins to test the hypothesis that AR interferes with Smad-activation through its interactions with accessory proteins involved with Smad recruitment to the receptor complex. In Aim 3, we will explore two different therapeutic strategies to block EMT signaling in animal models of PCO. First we will test the hypothesis that pharmacological blockade of AR is sufficient to prevent cellular changes associated with PCO development. In a second arm of this study, we will test the ability of a membrane-permeable form of Smad7, an inhibitor of Smad signaling, to attenuate EMT in our mouse model of PCO. We will also investigate a combination therapy involving combined use of an AR inhibitor and Tat-Smad7. These studies aim to clarify molecular mechanisms leading to PCO and lead to therapeutic strategies for its prevention.

项目摘要白内障是全球失明的主要原因之一。手术去除白内障镜头后，大约20％的白内障患者出现后囊腹盘（PCO），并显着显着生活质量受损。鉴于白内障的患病率和PCO的相对高率之后白内障手术，尤其是在发展更具侵略性PCO的年轻患者中增加开发PCO风险较高的糖尿病患者数量，迫切需要疗法以防止导致这种盲目条件的细胞变化。目前尚无医学疗法可有效防止 PCO，无替代囊膜切开术进行治疗。那就是这项工作的长期影响将解决目前未满足的临床需求 - 使用药物抑制生长因子的PCO预防PCO 信号负责PCO开发。转化生长因子β（TGF-β）被认为是一种驱动PCO发病机理的主要生长因子。 TGF-β诱导SMAD蛋白的激活，然后带来与上皮细胞向间质细胞转移有关的一系列基因的转录表型，称为上皮到间质转变（EMT）。在初步研究中，我们表明与糖尿病眼病相关的多元型途径醛酸（AR）促进了SMAD激活 TGF-β。拟议的研究旨在制定治疗策略，以中断驱动驱动的致病信号 PCO过程。在AIM 1中，我们将使用转基因鼠标模型来测试AR的假设促进PCO病原体中的EMT。 PCO开发的比较风险将在我们的AR-TG中衡量使用免疫染色和定量PCR到手术后的不同时间测量镜头的EMT和结构标记。在AIM 2中，我们将破译在PCO开发中将AR与TGFß介导的信号传导联系起来的机制。我们将利用突变形式的 AR和TGFß受体衔接蛋白，以测试AR通过SMAD激活通过它与与SMAD募集到接收器复合物有关的辅助蛋白的相互作用。在AIM 3中，我们将探索两种不同的治疗策略，以阻止PCO动物模型中的EMT信号传导。首先，我们会测试AR的药物阻滞足以防止相关细胞变化的假设与PCO开发。在这项研究的第二组中，我们将测试膜可渗透形式的能力 SMAD7是SMAD信号传导的抑制剂，可在我们的PCO小鼠模型中减弱EMT。我们还将调查联合疗法涉及AR抑制剂和TAT-SMAD7的联合使用。这些研究旨在澄清分子机制导致PCO并为预防提供治疗策略。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Protective Effect of Metformin Use on Early Nd:YAG Laser Capsulotomy.

DOI：
10.1167/iovs.62.10.24
发表时间：
2021-08-02
期刊：
Investigative ophthalmology & visual science
影响因子：
4.4
作者：
Patnaik JL;Christopher KL;Pedler MG;Shieh B;Petrash CC;Wagner BD;Mandava N;Lynch AM;Palestine AG;Petrash JM
通讯作者：
Petrash JM

Nanogel-Facilitated In-Situ Delivery of a Cataract Inhibitor.