Regulation of RPE degeneration by REV-ERBalpha

REV-ERBalpha 对 RPE 变性的调节

基本信息

  • 批准号:
    10029720
  • 负责人:
  • 金额:
    $ 53.32万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-08-01 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

Project Summary Degeneration of retinal pigment epithelium (RPE) causes vision loss in age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Promoting survival of RPE (and thereby photoreceptors) is critical for preserving vision. Whereas many factors contribute to RPE degeneration in eye diseases including both genetic and environmental ones, oxidative stress is one of the major contributors to RPE dysfunction and degeneration, derived primarily from excess mitochondrial oxidative products, and phagocytosis-related lipid oxidation. However, the processes through which dysregulated oxidative stress leads to RPE dysfunction and degeneration in eye diseases remain incompletely defined. Moreover, there is lack of effective approaches to promote RPE health and survival. Identification of the basic molecular links which sense RPE redox (reduction/oxidation) environment to impact RPE dysfunction and degeneration will aid in the identification of new molecular targets to rejuvenate endogenous cellular defense system in aging RPE and prevent vision loss in eye diseases. In this project we identified a redox-sensing nuclear receptor REV-ERBα, which may act as a transcriptional regulator linking RPE redox homeostasis and RPE antioxidant defense to impact RPE degeneration. REV-ERBα, functioning as a redox- and ligand-dependent transcription factor, controls multiple biological processes including cellular metabolism, inflammation, and circadian rhythm. Our preliminary results show that: 1) REV-ERBα levels decline with aging in RPE; 2) genetic deletion of REV-ERBα in mice leads to age-related development of RPE degeneration, with subretinal deposits, impaired visual function and dampened RPE phagocytic function; 3) RPE specific deletion of REV-ERBα causes similar fundus lesions; 4) REV-ERBα deficiency exacerbates chemically-induced induced RPE damage and retinal toxicity in vivo and in vitro; 4) activation of REV-ERBα protects RPE in vitro and in vivo; and 5) REV-ERBα directly regulates nuclear factor erythroid-2 related factor 2 (NRF2) transcription and its associated antioxidant genes. We hypothesize that REV-ERBα is a novel redox-sensitive regulator of RPE intracellular antioxidant defense system, and activating REV-ERBα is a new way to protect RPE. This hypothesis will be evaluated with both genetic and pharmacological approaches of modulating REV-ERBα in both acute and chronic models of RPE damage and degeneration. Mechanistically this work will explore whether REV-ERBα protects RPE vial enhancing RPE antioxidant self-defense. This proposed work will uncover novel molecular regulatory mechanisms underlying RPE degeneration, and new druggable molecular targets for developing improved strategies to counter RPE damage and degeneration in eye diseases.
项目摘要 视网膜色素上皮(RPE)变性导致老年性黄斑变性患者视力下降 (AMD)和视网膜色素变性(RP)。促进RPE(以及由此的光感受器)的存活对于视网膜的生长至关重要。 保持视力。然而,许多因素导致眼部疾病中的RPE变性,包括 由于遗传和环境因素,氧化应激是导致RPE功能障碍的主要因素之一, 变性,主要来源于过量的线粒体氧化产物和吞噬相关脂质 氧化然而,氧化应激失调导致RPE功能障碍的过程, 眼病中的变性仍然没有完全确定。此外,缺乏有效的办法, 促进RPE健康和存活。识别感知RPE氧化还原的基本分子链 影响RPE功能障碍和变性的氧化(还原/氧化)环境将有助于识别 新的分子靶点,以恢复老化RPE中的内源性细胞防御系统并防止视力丧失 眼睛疾病。在这个项目中,我们鉴定了一种氧化还原敏感核受体REV-ERBα,它可能作为一种 连接RPE氧化还原稳态和RPE抗氧化防御影响RPE的转录调节因子 退化REV-ERBα作为一种氧化还原和配体依赖性转录因子,控制多个 生物过程包括细胞代谢、炎症和昼夜节律。我们的初步结果 结果表明:1)REV-ERBα水平随着RPE的衰老而下降; 2)小鼠中REV-ERBα的基因缺失导致 与年龄相关的RPE变性发展,伴有视网膜下沉积,视觉功能受损, RPE吞噬功能减弱; 3)RPE特异性REV-ERBα缺失导致类似眼底病变; 4) REV-ERBα缺乏可加重体内和体外化学诱导的RPE损伤和视网膜毒性 REV-ERBα的激活在体外和体内保护RPE; 5)REV-ERBα直接调节细胞核的增殖。 红细胞2因子相关因子2(NRF 2)转录及其相关的抗氧化基因。我们假设 REV-ERBα是RPE细胞内抗氧化防御系统的一种新的氧化还原敏感性调节剂, 激活REV-ERBα是保护RPE的新途径。这一假设将与遗传和 在急性和慢性RPE损伤模型中调节REV-ERBα的药理学方法, 退化从机制上讲,这项工作将探讨REV-ERBα是否通过增强RPE来保护RPE 抗氧化自我防御这项工作将揭示新的分子调控机制, RPE变性和新的药物分子靶点,用于开发对抗RPE的改进策略 眼睛疾病的损害和退化。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

JING CHEN其他文献

JING CHEN的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('JING CHEN', 18)}}的其他基金

Establishing A New Diagnostic Paradigm for Peripheral Artery Disease among Patients with Chronic Kidney Disease
建立慢性肾病患者周围动脉疾病的新诊断范式
  • 批准号:
    10465042
  • 财政年份:
    2021
  • 资助金额:
    $ 53.32万
  • 项目类别:
Establishing A New Diagnostic Paradigm for Peripheral Artery Disease among Patients with Chronic Kidney Disease
建立慢性肾病患者周围动脉疾病的新诊断范式
  • 批准号:
    10677577
  • 财政年份:
    2021
  • 资助金额:
    $ 53.32万
  • 项目类别:
Establishing A New Diagnostic Paradigm for Peripheral Artery Disease among Patients with Chronic Kidney Disease
建立慢性肾病患者周围动脉疾病的新诊断范式
  • 批准号:
    10186101
  • 财政年份:
    2021
  • 资助金额:
    $ 53.32万
  • 项目类别:
Regulation of RPE degeneration by REV-ERBalpha
REV-ERBalpha 对 RPE 变性的调节
  • 批准号:
    10667553
  • 财政年份:
    2020
  • 资助金额:
    $ 53.32万
  • 项目类别:
Regulation of RPE degeneration by REV-ERBalpha
REV-ERBalpha 对 RPE 变性的调节
  • 批准号:
    10218186
  • 财政年份:
    2020
  • 资助金额:
    $ 53.32万
  • 项目类别:
Regulation of RPE degeneration by REV-ERBalpha
REV-ERBalpha 对 RPE 变性的调节
  • 批准号:
    10448503
  • 财政年份:
    2020
  • 资助金额:
    $ 53.32万
  • 项目类别:
Wnt signaling-mediated control of blood-retinal barrier
Wnt信号介导的血视网膜屏障控制
  • 批准号:
    9918370
  • 财政年份:
    2017
  • 资助金额:
    $ 53.32万
  • 项目类别:
Clinical Research and Community Engagement Core
临床研究和社区参与核心
  • 批准号:
    10504810
  • 财政年份:
    2016
  • 资助金额:
    $ 53.32万
  • 项目类别:
Clinical Research and Community Engagement Core
临床研究和社区参与核心
  • 批准号:
    10664045
  • 财政年份:
    2016
  • 资助金额:
    $ 53.32万
  • 项目类别:
Urinary Angiotensinogen Excretion and Salt-Sensitivity of Blood Pressure
尿血管紧张素原排泄和血压的盐敏感性
  • 批准号:
    8697725
  • 财政年份:
    2014
  • 资助金额:
    $ 53.32万
  • 项目类别:

相似海外基金

Improving Acute Disease Management for Patients with Alzheimer's Disease and Related Dementias
改善阿尔茨海默病和相关痴呆症患者的急性疾病管理
  • 批准号:
    10712647
  • 财政年份:
    2001
  • 资助金额:
    $ 53.32万
  • 项目类别:
INDUCTION OF ACUTE DISEASE IN MACAQUES BY NEF GENE VARIANT OF SIVMAC239
SIVMAC239 的 NEF 基因变体在猕猴中诱导急性疾病
  • 批准号:
    6247642
  • 财政年份:
    1997
  • 资助金额:
    $ 53.32万
  • 项目类别:
INDUCTION OF ACUTE DISEASE IN MACAQUES BY NEF GENE VARIANT OF SIVMAC239
SIVMAC239 的 NEF 基因变体在猕猴中诱导急性疾病
  • 批准号:
    3718999
  • 财政年份:
  • 资助金额:
    $ 53.32万
  • 项目类别:
Neurophysiological alterations in multiple sclerosis patients during acute disease acivity
多发性硬化症患者急性疾病活动期间的神经生理学变化
  • 批准号:
    465668867
  • 财政年份:
  • 资助金额:
    $ 53.32万
  • 项目类别:
    Research Grants
SIVMAC 1NEF ALLELE: LYMPHOCYTE ACTIVATION & ACUTE DISEASE IN MACAQUE MONKEYS
SIVMAC 1NEF 等位基因:淋巴细胞激活
  • 批准号:
    3719026
  • 财政年份:
  • 资助金额:
    $ 53.32万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了