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:
  • 金额:
    $ 39.09万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(2)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Lianwang Guo其他文献

Lianwang Guo的其他文献

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{{ truncateString('Lianwang Guo', 18)}}的其他基金

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
  • 财政年份:
    2021
  • 资助金额:
    $ 39.09万
  • 项目类别:
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:
    10132335
  • 财政年份:
    2021
  • 资助金额:
    $ 39.09万
  • 项目类别:
BET Bromodomain proteins as Novel Epigenetic Targets for prevention of Intimal Hyperplasia after Vascular Surgery
BET 溴结构域蛋白作为预防血管手术后内膜增生的新表观遗传靶点
  • 批准号:
    10298010
  • 财政年份:
    2020
  • 资助金额:
    $ 39.09万
  • 项目类别:
Development of unimolecular nanoparticle-mediated periadventitial drug delivery system for sustained and targeted inhibition of intimal hyperplasia following open vascular reconstruction
开发单分子纳米粒子介导的外膜周围药物递送系统,用于持续和靶向抑制开放血管重建后的内膜增生
  • 批准号:
    10305283
  • 财政年份:
    2020
  • 资助金额:
    $ 39.09万
  • 项目类别:
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
  • 财政年份:
    2019
  • 资助金额:
    $ 39.09万
  • 项目类别:
Sigma-1 Chaperone-Mediated in vivo Neuroprotection in the Retina
Sigma-1 伴侣介导的体内视网膜神经保护
  • 批准号:
    9513208
  • 财政年份:
    2012
  • 资助金额:
    $ 39.09万
  • 项目类别:
Sigma-1 Chaperone-Mediated in vivo Neuroprotection in the Retina
Sigma-1 伴侣介导的体内视网膜神经保护
  • 批准号:
    8346582
  • 财政年份:
    2012
  • 资助金额:
    $ 39.09万
  • 项目类别:
Sigma-1 Chaperone-Mediated in vivo Neuroprotection in the Retina
Sigma-1 伴侣介导的体内视网膜神经保护
  • 批准号:
    8700417
  • 财政年份:
    2012
  • 资助金额:
    $ 39.09万
  • 项目类别:
Sigma-1 Chaperone-Mediated in vivo Neuroprotection in the Retina
Sigma-1 伴侣介导的体内视网膜神经保护
  • 批准号:
    8523895
  • 财政年份:
    2012
  • 资助金额:
    $ 39.09万
  • 项目类别:
Sigma-1 Chaperone-Mediated in vivo Neuroprotection in the Retina
Sigma-1 伴侣介导的体内视网膜神经保护
  • 批准号:
    9117592
  • 财政年份:
    2012
  • 资助金额:
    $ 39.09万
  • 项目类别:

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