权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10376193
负责人：
Lianwang Guo
金额：
$ 39.09万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-01-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10376193
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 Persons 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 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 innovation macrophage mouse model novel novel strategies overexpression preservation prevent retinal neuron retinal rods success transcription factor

项目摘要

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.

项目总结