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.
项目概要 伴有皮质下梗死和白质脑病的常染色体主导性脑动脉病 (CADASIL) 是一种 常见小血管病 (SVD),其特征是微血管功能障碍导致缺血 中风和血管性痴呆。 CADASIL 是由光滑细胞表达的 NOTCH3 基因突变引起的。 肌细胞 (SMC),与较大的脉管系统(如动脉/小动脉)和周细胞相关 包裹毛细血管。这些突变诱导细胞外受体聚集和复合物形成 其他蛋白质包括基质金属蛋白酶抑制剂 TIMP3。因此 TIMP3 聚集在 微循环导致脑血流(CBF)调节受损。 TIMP3 积累的下游, 其病理机制包括表皮生长因子受体 (EGFR) 抑制,导致 神经血管耦合 (NVC) 和 ATP 产生。虽然这种病理机制已在其他疾病中得到研究 血管细胞类型(内皮细胞和 SMC)、周细胞仍未得到充分研究。 周细胞是一个丰富的、高度异质的群体,其中包括显示速度快的网状周细胞 开/关收缩反应通常驻留在 1-4 阶毛细血管上。最近的研究揭示了 KATP 与微血管域中的其他细胞相比,Kir6.1 通道在周细胞中独特地高表达。 该通道已被证明与 CBF 调节高度相关,其中低 ATP 激活通道, 导致周细胞超极化,随后血管舒张,增强局部脑灌注以满足能量需求 需求。由于 CADASIL 早期出现神经血管功能障碍,本提案重点关注网格 周细胞及其损伤。 我的初步数据表明,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,需要进一步表征通道 阐明潜在的治疗目标。具体来说,TIMP3 和 EGFR 信号传导如何影响 Kir6.1 通道 活动。该提案的第一个目标是使用双峰方法来表征 Kir6.1 通道属性 脑网状周细胞的功能和表达。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外源应用和遗传 击倒。该目标还将采用通过 EGFR 配体 HB-EGF 的救援技术来恢复 Kir6.1 通道 功能,由于其在大脑周细胞中的突出表达,可能是恢复 CBF 失调的关键 在卡达西尔。该提案的完成将填补涉及脑网的文献的重大空白 周细胞和破坏性脑血管疾病 CADASIL 目前无法治愈且有限 治疗方案。

项目成果

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