Degrading BET Proteins is Neuroprotective in Ischemic Stroke

降解 BET 蛋白对缺血性中风具有神经保护作用

基本信息

  • 批准号:
    9760445
  • 负责人:
  • 金额:
    $ 3.92万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-04-01 至 2021-03-31
  • 项目状态:
    已结题

项目摘要

PROJECT DESCRIPTION Neuroinflammation after stroke significantly contributes to neuronal cell death. Bromodomain and Extra Terminal Domain (BET) proteins are essential to inflammatory gene transcription. There are four BET proteins: BRD2, BRD3, BRD4, and BRDT. BRD2 and BRD4 are abundant and ubiquitously expressed. BRD3 expression is very low in most tissues including the brain, and BRDT is testis specific. BET proteins contain two conserved bromodomains that associate with acetylated lysines, and an extraterminal domain. BET proteins have varied effects including chromatin remodeling, histone acetyltransferase activity, and as scaffolds to recruit transcription factors; they couple chromatin remodeling with transcription. We hypothesize that BET blockade will provide a multipronged approach to reducing cell death after stroke. BRD2 normally represses peroxisome proliferator activator γ (PPARγ) activity, which has an anti-inflammatory effect, so we expect that inhibiting BRD2 will increase anti-inflammatory gene transcription. BRD2 knockdown also decreases nuclear factor-κB (NF-κB) activation, which is a major regulator of pro-inflammatory gene transcription in stroke. BRD4 acts as an NF-κB co-activator, therefore we predict that BRD2 and BRD4 inhibition will decrease pro-inflammatory gene transcription in the ischemic brain. Furthermore, because BRD2 and BRD4 constitutively inhibit nuclear factor (erythroid-derived 2)-related factor (Nrf2) which is essential to antioxidant gene transcription, we expect BRD2/4 inhibition to increase expression of antioxidant genes, reducing oxidative stress. Little is known regarding the role of BET proteins in stroke, but our preliminary data shows that BET inhibition reduces infarct in a rodent model of stroke. Our long-term goal is to reduce the spread of stroke damage by limiting the effects of secondary inflammation. Our hypothesis is that BET inhibition is neuroprotective in ischemic stroke by limiting the deleterious effects of secondary inflammation. Our main objective is to determine the mechanism by which BET inhibition is protective in ischemic stroke. In Aim 1, we will determine the neuroprotective effect of BET blockade after ischemia using dBET1 (a proteolysis- targeting chimera that degrades BET proteins). We will utilize male mice subjected to ischemic stroke to investigate the effects of BET blockade on infarct size and long-term behavioral outcomes. In Aim 2, we will determine the effects of BET blockade on stroke-induced neuroinflammation. This project will provide mechanistic insights into how BET proteins contribute to secondary injury after ischemic stroke. These data will yield a positive impact as it will provide a strong foundation for future development of novel therapeutic strategies targeting BET proteins to reduce stroke damage.
项目描述

项目成果

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Kelly M DeMars其他文献

Kelly M DeMars的其他文献

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{{ truncateString('Kelly M DeMars', 18)}}的其他基金

Degrading BET Proteins is Neuroprotective in Ischemic Stroke
降解 BET 蛋白对缺血性中风具有神经保护作用
  • 批准号:
    9906760
  • 财政年份:
    2019
  • 资助金额:
    $ 3.92万
  • 项目类别:

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