Pericyte KATP channel hyperactivity in cerebral small vessel disease

脑小血管疾病中周细胞 KATP 通道过度活跃

基本信息

  • 批准号:
    10750246
  • 负责人:
  • 金额:
    $ 3.91万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-07-16 至 2026-07-15
  • 项目状态:
    未结题

项目摘要

Project Summary Cerebral Autosomal Dominate Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a common small vessel disease (SVD) that is characterized by microvascular dysfunction leading to ischemic stroke and vascular dementia. CADASIL is caused by mutations in the NOTCH3 gene expressed by smooth muscle cells (SMCs), that are associated with larger vasculature such as arteries/arterioles, and pericytes that wrap around capillaries. These mutations induce extracellular receptor aggregation and complex formation with other proteins including matrix metalloproteinase inhibitor, TIMP3. TIMP3 therefore accumulates around the microcirculation causing impaired cerebral blood flow (CBF) regulation. Downstream of TIMP3 accumulation, the pathomechanism includes epidermal growth factor receptor (EGFR) inhibition, resulting in decreased neurovascular coupling (NVC) and ATP production. While this pathomechanism has been investigated in other vascular cell types (endothelial cells and SMCs), pericytes remain understudied. Pericytes are an abundant, highly heterogenous population, that includes mesh pericytes which display fast on/off contractile responses and typically reside on 1-4th order capillaries. Recent studies have revealed a KATP channel, Kir6.1, is uniquely highly expressed in pericytes compared to other cells in the microvascular domain. This channel has proven to be highly relevant in CBF regulation where activation of the channel from low ATP, results in pericyte hyperpolarization, ensuing vasodilation to enhance regional cerebral perfusion to meet energy demands. Due to the CADASIL’s early presentation of neurovascular dysfunction, this proposal focuses on mesh pericytes and their impairment. My preliminary data show that, in CADASIL, mesh pericyte Kir6.1 channels are hyperactive in basal conditions, indicating dysregulation of channel activity. However further characterization of the channel is needed to elucidate potential treatment targets. Specifically, how TIMP3 and EGFR signaling influence Kir6.1 channel activity. This proposal’s first Aim is to characterize Kir6.1 channel properties using a bimodal approach looking at both function and expression in cerebral mesh pericytes. The goal of the second Aim is to expose the mechanism underlying Kir6.1 channel dysfunction including TIMP3 exogenous application and genetic knockdown. This Aim will also employ rescue techniques via EGFR ligand, HB-EGF, to restore Kir6.1 channel function, which due to its prominent expression in cerebral pericytes may be key to restoring CBF dysregulation in CADASIL. Completion of this proposal will fill a significant gap in the literature involving cerebral mesh pericytes and the devastating cerebrovascular disease, CADASIL which currently has no cure and limited treatment options.
项目摘要 常染色体显性脑动脉病合并皮质下梗塞和白质脑病(CADASIL) 常见的小血管疾病(SVD),其特征是导致缺血的微血管功能障碍 中风和血管性痴呆。CADASIL是由Smooth表达的NOTCH3基因突变引起的 肌细胞(SMC),与较大的血管系统相关,如动脉/小动脉,以及周细胞, 将毛细血管包裹起来。这些突变诱导细胞外受体聚集和与 其他蛋白质包括基质金属蛋白酶抑制因子TIMP3。因此,TIMP3累积在 导致脑血流(CBF)调节受损的微循环。在TIMP3积累的下游, 其发病机制包括抑制表皮生长因子受体(EGFR),导致细胞数量减少。 神经血管偶联(NVC)和ATP的产生。虽然这种致病机制已经在其他地方进行了研究 血管细胞类型(内皮细胞和平滑肌细胞)、周细胞仍未得到充分研究。 周细胞是一个丰富的、高度异质性的群体,包括快速显示的网状周细胞。 开/关收缩反应,通常驻留在1-4级毛细血管上。最近的研究揭示了一种KATP 与微血管领域中的其他细胞相比,ChannelKir6.1在周细胞中的表达水平是唯一的。 该通道已被证明在CBF调节中高度相关,其中通道从低ATP激活, 结果周细胞超极化,随之而来的是血管扩张,增强局部脑血流以满足能量需求 要求。由于CADASIL早期表现为神经血管功能障碍,本建议重点介绍MESH 周细胞及其损伤。 我的初步数据显示,在CADASIL中,网状周细胞Kir6.1通道在基础条件下过度活跃, 表明通道活动失调。然而,需要对通道进行进一步的表征以 阐明潜在的治疗目标。具体地说,TIMP3和EGFR信号如何影响Kir6.1通道 活动。该建议的第一个目标是使用双峰方法来表征Kir6.1信道属性 在大脑网状周细胞中的功能和表达。第二个目标的目标是揭露 Kir6.1通道功能障碍的机制包括TIMP3的外源性应用和遗传学 击倒对手。这个目标还将使用通过EGFR配体HB-EGF的救援技术来恢复Kir6.1通道 由于其在脑周细胞中的显著表达,其功能可能是恢复脑血流紊乱的关键 在CADASIL。这项建议的完成将填补有关大脑网状网的文献中的一个重大空白 周细胞与毁灭性的脑血管疾病CADASIL,目前尚无治愈和限制 治疗方案。

项目成果

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