Endothelial Cell Epigenetics and Blood-Brain Barrier.

内皮细胞表观遗传学和血脑屏障。

• 批准号: 10182212
• 负责人: Peeyush Kumar Thankamani Pandit
• 金额: $ 49.68万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10182212
• 关键词: Adult; Agonist; Angiogenesis Pathway; Blood - brain barrier anatomy; Blood Vessels; Brain; Cellular biology; Central Nervous System Diseases; Cerebrum; Clinical; Clinical Trials; Complex; Data; Development; Disease; Embryo; Endothelial Cells; Enzymes; Epigenetic Process; Evaluation; Gene Expression; Gene Expression Profile; Gene Silencing; Genes; Genetic Transcription; Genome; Goals; HDAC2 gene; Histones; Impairment; Injury; Interdisciplinary Study; Knowledge; Ligands; Measures; Mediating; Modeling; Natural regeneration; Neuraxis; Neurologic; Neuronal Injury; Outcome; Pathology; Pathway interactions; Patients; Pattern; Pharmacology; Phenotype; Polycomb; Recovery; Repression; Research; Role; Signal Pathway; Stroke; Testing; Therapeutic; Time; Tracer; angiogenesis; base; beta catenin; blood-brain barrier disruption; blood-brain barrier function; brain endothelial cell; cerebrovascular; clinically relevant; effective intervention; epigenetic silencing; experimental study; functional loss; functional outcomes; gene repression; histone deacetylase 2; improved; improved outcome; inhibitor/antagonist; insight; new therapeutic target; novel; novel therapeutics; post stroke; prevent; programs; repaired; reparative capacity; stroke model; stroke patient; stroke therapy; targeted treatment; transcription factor; transcriptome; transcriptome sequencing; vascular factor

PROJECT SUMMARY/ABSTRACT: Several clinical trials targeting neuronal injury have failed to demonstrate significant benefit in stroke patients. Recent studies suggest that there is a significant vascular component to poor functional outcomes after stroke, particularly post-stroke blood-brain barrier (BBB) disruption. Currently no treatments available to treat leaky BBB and rejuvenate central nervous system (CNS) vessels after stroke. Here we propose two different approaches to reach this goal. Aim 1: Gene expression patterns are set, in part, by epigenetic processes that classify the genome into active and silent to support the development and differentiation. Nearly nothing is known about the epigenetic mechanisms that govern the development of BBB. This approach is based on the central premise that understanding the epigenetic mechanisms that regulate the formation of an intact BBB could identify novel targets to modulate BBB. Interestingly, in our preliminary experiment, we found that during development some important BBB genes are transcriptionally repressed in adult CNS endothelial cells (ECs-epicenter of BBB). Further, we discovered that the two major epigenetic enzymes histone deacetylate 2 (HDAC2) and polycomb repressive complex 2 (PRC2) mediate this transcriptional repression. Based on these novel findings, we propose that, during embryonic brain development, the epigenetic regulators HDAC2 and PRC2 establish an intact BBB via transcriptional repression of specific BBB genes. Further, we hypothesize that, while this expression profile is essential for maintaining a functional BBB in adults, it also contributes to impaired BBB repair by CNS ECs following stroke. This study will identify the epigenetic regulators HDAC2 and PRC2 as new therapeutic targets to manipulate BBB during disease and therapy and will advance current knowledge regarding BBB development. Aim 2: Our second approach is to target a core signaling pathway in cerebral vessels. During early brain development, the Wnt/β-catenin pathway orchestrates BBB development and CNS angiogenesis. However, the Wnt/β- catenin pathway diminishes during later vessel development and is almost inactive in adult CNS ECs, making it difficult to target this pathway for vascular repair in CNS diseases. Our new preliminary data demonstrate the epigenetic mechanism behind Wnt pathway inactivation in adult CNS ECs and show that the Wnt pathway can be re-activated in adult CNS ECs by epigenetic manipulation and Wnt ligand stimulation. Consequently, we hypothesize that reactivating the Wnt/β- catenin pathway in adult CNS ECs will restore the developmental phenotypes including BBB formation and angiogenesis in adult CNS ECs, thereby promoting BBB repair and vascular regeneration after stroke. The Wnt pathway, for a long time been said to be undruggable owing to its absence in adult vessels, our evaluations on targeting the Wnt pathway for BBB repair will shift the mindset, leading to targeting this pathway for CNS and other diseases. If successful this proposal will pave the way for the development of novel epigenetic and Wnt-targeting therapies to repair the BBB and improve outcomes in stroke patients. The overall impact of the project is high as it proposes a broadly applicable strategy to repair BBB which is central to several CNS disorders.

项目总结/摘要： 几项针对神经元损伤的临床试验未能证明中风患者的显著益处。 最近的研究表明，卒中后功能预后不良与血管因素有关， 中风后血脑屏障（BBB）破坏。目前没有治疗方法可用于治疗血脑屏障渗漏和恢复活力 中枢神经系统（CNS）血管卒中后。在这里，我们提出了两种不同的方法来实现这一目标。 目的1：基因表达模式的设定，部分是通过表观遗传过程，将基因组分为活性基因组和非活性基因组。 并默默地支持发展和差异化。几乎没有什么是已知的表观遗传机制， 控制BBB的发展。这种方法基于一个中心前提，即理解表观遗传 调节完整BBB形成的机制可以鉴定调节BBB的新靶点。有趣的是，在 我们的初步实验发现，在发育过程中，一些重要的BBB基因被转录抑制， 在成体CNS内皮细胞（EC-BBB的中心）中。此外，我们发现两种主要的表观遗传酶 组蛋白去乙酰化物2（HDAC 2）和多梳抑制复合物2（PRC 2）介导这种转录抑制。基于 基于这些新的发现，我们提出，在胚胎脑发育过程中，表观遗传调节因子HDAC 2和 PRC 2通过特异性BBB基因的转录抑制建立完整的BBB。此外，我们假设，虽然这 表达谱对于维持成年人功能性BBB是必需的，它也有助于受损的BBB修复由CNS 中风后的内皮细胞。这项研究将确定表观遗传调节因子HDAC 2和PRC 2作为新的治疗靶点， 在疾病和治疗期间操纵BBB，并将推进关于BBB发展的现有知识。 目的2：我们的第二种方法是靶向脑血管中的核心信号通路。早期脑 在BBB发育和CNS血管生成中，Wnt/β-连环蛋白途径协调BBB发育和CNS血管生成。然而，Wnt/β- 连环蛋白途径在后期血管发育过程中减少，在成年CNS EC中几乎不活动，使得难以 靶向该通路用于CNS疾病中的血管修复。我们新的初步数据表明， 在成年CNS EC中Wnt通路失活的背后，并显示Wnt通路可以在成年CNS EC中重新激活。 通过表观遗传操作和Wnt配体刺激。因此，我们假设重新激活Wnt/β- 成人CNS EC中的catenin通路将恢复发育表型，包括BBB形成和血管生成 在成年CNS EC中，从而促进脑卒中后BBB修复和血管再生。Wnt信号通路， 由于其在成人血管中的缺失，我们对靶向Wnt通路的BBB的评价被认为是不可用的， 修复将改变思维方式，导致靶向中枢神经系统和其他疾病的这一途径。 如果成功，这一提议将为开发新的表观遗传和Wnt靶向药物铺平道路。 治疗以修复BBB并改善卒中患者的结局。该项目的整体影响是高的，因为它 提出了一种广泛适用的策略来修复BBB，这是几种CNS疾病的核心。