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.

项目概要 色素性视网膜炎 (RP) 是导致遗传性失明的主要原因，每 3500 人中就有一人患有遗传性失明。 对于 RP 没有有效的治疗方法，也没有治愈的前景，因为单独治疗尚不可行 纠正导致光感受器死亡的 >2000 个突变（分布在约 70 个基因中）。 最近在 RP 模型和 RP 患者中发现了小胶质细胞介导的致病过程 视网膜小胶质细胞在视杆细胞退化之前转变为炎症状态。 激活的小胶质细胞在正反馈回路中大量减少视杆细胞，从而放大次级视锥细胞的损失。 克罗胶质细胞炎症激活是一种早期常见的致病事件，会损害视杆细胞，阻止其发生 我们的长期目标应该是减轻视杆细胞退化，从而保护 RP 患者的视锥细胞和日间视力。 的目的是确定控制视网膜小胶质细胞转变为炎症状态的主分子开关，因此 旨在建立一个新的干预目标来广泛治疗 RP，无论其遗传原因如何。 做出了令人兴奋的初步发现，Bromo 和 Extra-Terminal (BET) 蛋白质家族可能代表 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 它可以阻止小胶质细胞炎症转变并保护光感受器的存活。 报告称，阻断整个 BET 家族可消除视网膜小胶质细胞炎症并减轻光感受器 RD10 小鼠模型中 RP 蛋白缺失，每个蛋白都含有两个乙酰基组蛋白结合溴结构域。 在致病刺激下，BET 蛋白会与关键的转录物组装起来。 细胞状态特异性中一组选定的致病基因的转录因子，并共同激活其表达 方式研究控制静息状态到炎症状态转变的BET调节机制。 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 BET 功能 (Aim-2) 以及 BET 相关关键转录因子的结构域 考虑到 BET 系列不仅仅是另一个冗余，该提案具有创新性。 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，从逻辑上讲，BET 靶向应该能够更有效地抑制小胶质细胞炎症并提供保护 该项目最终将导致表观遗传学靶向“表观药物疗法”的新范例。 apy”可有效减轻 RP，而无需针对个体突变和下游路径进行基因靶向 由于小胶质细胞炎症是视网膜退行性疾病的一个标志，因此这项研究将具有广泛的意义。 对数百万患有 RP 以外疾病的患者产生影响。