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: 10306197
• 负责人: Lianwang Guo
• 金额: $ 34.54万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10306197
• 关键词: Master; epigenetic; regulators; retinal; degenerative

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 视网膜色素变性（RP）是遗传性失明的主要原因，每3500人中就有一人患病。那里 没有有效的治疗RP，也没有治愈的前景，因为它还没有实际的个人 纠正启动感光细胞死亡的>2000个突变（分布在~70个基因中）。另一方面，com- 最近已经在RP模型和具有以下特征的患者中鉴定了单核小胶质细胞介导的致病过程： 不同的突变。视网膜小胶质细胞在视杆细胞变性前转化为炎症状态。这些 激活的小神经胶质细胞在正反馈回路中减少视杆细胞，从而放大次级视锥细胞损失。作为我- croglial炎症激活是一种早期和常见的致病事件，对杆有害，阻断它 应减弱视杆变性，从而保留RP患者的视锥细胞和日间视力。我们的长期目标 是为了确定一个控制视网膜小胶质细胞转化为炎症状态的主分子开关， 从而建立一种新的介入靶点，广泛治疗RP，无论其遗传原因如何。我们有 一个令人兴奋的初步发现，溴和额外的终端（BET）家族的蛋白质可能代表 这样一个新的目标。我们的中心假设是BET家族是一个主要的表观遗传开关，抑制了细胞的增殖。 其阻断小胶质细胞炎性转变并保护感光细胞存活。我们是第一个 报告说，阻断整个BET家族消除视网膜小胶质细胞炎症，减轻感光细胞 RP的rd 10小鼠模型中的损失。BET蛋白每个含有两个乙酰基-组蛋白结合布罗莫结构域 可以被屏蔽的东西。在病原体刺激下，BET蛋白质与关键的转录因子组装， 转录因子在细胞状态特异性的一组选择的致病基因上，并共同激活其表达。 方式为了研究BET调节机制，控制静息状态向炎症状态的转变， 小胶质细胞，我们将描述哪些BET蛋白决定小胶质细胞炎症（Aim-1），并定义溴- 负责该BET功能的结构域（Aim-2）以及BET相关的关键转录因子， tor（s）（Aim-3）.考虑到BET家族不仅仅是另一个冗余， 下游通路。相反，它是致病细胞状态转变的上游表观遗传决定因素。 因此，BET靶向应该在逻辑上导致更有效地抑制小胶质细胞炎症和保护 光感受器。该项目将最终导致一个新的范式表观遗传靶向“表观药物治疗， “有效地减轻RP，而不必在基因上靶向个体突变和下游路径- 的方式由于小胶质细胞炎症是视网膜退行性疾病的标志，因此这项研究将具有广泛的应用前景。 影响了数百万RP以外的患者。