Master epigenetic regulators and retinal degenerative disease

掌握表观遗传调节因子和视网膜退行性疾病

• 批准号: 9884774
• 负责人: Lianwang Guo
• 金额: $ 3.84万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2020-07-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9884774
• 关键词: Affect; American; Attenuated; Behavior; Binding; Blindness; Bromodomain; CCL2 gene; Cells; Cessation of life; Clinical Trials; Clustered Regularly Interspaced Short Palindromic Repeats; Co-Immunoprecipitations; Cone; Data; Epigenetic Process; Event; Family; Feedback; Genes; Genetic; Genetic Transcription; Goals; Histones; Immune; In Vitro; Individual; Inflammation; Inflammatory; Inherited; Interleukin-6; Intervention; Knock-out; Lead; LoxP-flanked allele; Mass Spectrum Analysis; Mediating; Messenger RNA; Microglia; Modeling; Molecular; Mus; Mutagenesis; Mutation; Outcome; Pathogenicity; Pathway interactions; Patients; Phagocytosis; Pharmacology; Pharmacotherapy; Photoreceptors; Play; Process; Protein Family; Proteins; RANTES; Reader; Reading; Reporting; Research; Rest; Retina; Retinal Degeneration; Retinitis Pigmentosa; Rod; Role; STAT3 gene; Safety; TNF gene; Tertiary Protein Structure; Validation; Vision; Western Blotting; activating transcription factor 3; cell type; chromatin immunoprecipitation; cytokine; effective therapy; gene therapy; genome-wide analysis; hereditary blindness; in vivo; inhibitor/antagonist; innovation; macrophage; mouse model; novel; novel strategies; overexpression; preservation; prevent; retinal neuron; retinal rods; success; transcription factor

Project summary Retinitis pigmentosa (RP) is the leading cause of inherited blindness afflicting one in every 3500 people. There are no effective treatments for RP, and no prospects for a cure either as it is not yet practical to individually correct the >2000 mutations (spread in ~70 genes) that initiate photoreceptor death. On the other hand, a com- mon microglia-mediated pathogenic process has been recently identified among RP models and patients with diverse mutations. Retinal microglia transform into an inflammatory state preceding rod degeneration. These activated microglia decimate rods in a positive feedback loop thereby amplifying secondary cone loss. As mi- croglial inflammatory activation is an early and common pathogenic event detrimental to rods, blocking it should attenuate rod degeneration thereby preserving cones and day vision in RP patients. Our long-term goal is to identify a master molecular switch governing the retinal microglial transition into the inflammatory state, so as to establish a novel interventional target for broadly treating RP regardless of the genetic cause. We have made an exciting preliminary finding that the Bromo and Extra-Terminal (BET) family of proteins may represent such a novel target. Our central hypothesis is that the BET family is a master epigenetic switch, inhibition of which blocks the microglial inflammatory transition and protects photoreceptor survival. We were the first to report that blocking the entire BET family abrogates retinal microglial inflammation and mitigates photoreceptor loss in the rd10 mouse model of RP. BET proteins each contains two acetyl-histone binding bromodomains that can be pharmacologically blocked. Upon pathogenic stimulation, BET proteins assemble with key tran- scription factors at, and co-activate the expression of, a select set of pathogenic genes in a cell state-specific manner. To investigate the BET regulatory mechanism governing the resting-to-inflammatory state transition of microglia, we will delineate which BET protein(s) dictate microglial inflammation (Aim-1), and define the bromo- domain(s) responsible for this BET function (Aim-2) as well as the BET-associated key transcription fac- tor(s)(Aim-3). This proposal is innovative considering that the BET family is not merely another redundant downstream pathway. Rather, it is an upstream epigenetic determinant of pathogenic cell state transition. Thus, BET targeting should logically lead to more effective inhibition of microglial inflammation and protection of photoreceptors. This project will ultimately lead to a new paradigm of epigenetically targeted “epi-drug ther- apy” to effectively mitigate RP without having to genetically target individual mutations and downstream path- ways. As microglial inflammation is a hallmark of retinal degenerative diseases, this research will have a broad impact on millions of patients with conditions beyond RP.

项目摘要 色素性视网膜炎（RP）是遗传失明的主要原因，每3500人中有一个。那里 对RP没有有效的治疗方法，也没有治愈的前景 纠正引发感光体死亡的> 2000突变（以〜70个基因扩散）。另一方面，一个 MON小胶质细胞介导的致病过程最近已在RP模型中发现 多样化的突变。视网膜小胶质细胞转变为棒状棒变性的炎症状态。这些 活化的小胶质细胞在正反馈回路中脱糖杆，从而扩大了次级锥体损失。如 腹膜炎症激活是杆的早期且常见的致病事件检测器，阻止了它 应减弱杆变性，从而保留RP患者的锥体和日视视线。我们的长期目标 是要确定一个管理视网膜小胶质细胞过渡到炎症状态的主分子开关，因此 为了建立一个新颖的介入靶标，用于广泛处理RP，无论遗传原因如何。我们有 提出了令人兴奋的初步发现，即Bromo和末端（BET）蛋白质可能代表 如此新颖的目标。我们的核心假设是，BET家族是主遗传转换，抑制 阻断小胶质细胞炎症过渡并保护感光器的存活率。我们是第一个 报告阻止整个BET家族废除常规小胶质细胞注入并减轻感光器 RD RP的RD10小鼠模型的损失。 BET蛋白每个都包含两个乙酰基酮结合溴ab骨 这可以被药物阻塞。在致病性刺激后，BET蛋白质与钥匙tran组装 脚本因子在细胞状态特异性中的一组病原基因的表达和共同激活 方式。调查负责静止到炎症状态过渡的BET调节机制 小胶质细胞，我们将描绘出蛋白质决定小胶质细胞注射（AIM-1），并定义溴 - 负责此BET功能（AIM-2）的域以及与BET相关的密钥转录FAC- Tor（S）（AIM-3）。考虑到BET家族不仅是另一个多余的，该提议具有创新性 下游路径。相反，它是致病细胞态过渡的上游表观遗传决定因素。 这一点，赌注定位应在逻辑上导致对小胶质注射和保护的更有效抑制 光感受器。该项目最终将导致一个新的以表观遗传为目标的“ Epi-Prug Ther- apy”以有效地减轻RP，而无需一定要靶向单个突变和下游路径 - 方式。由于小胶质细胞炎症是永久性疾病的标志，因此这项研究将具有广泛的 对数百万RP状况的患者的影响。