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

• 批准号: 10750246
• 负责人: Danielle A Jeffrey
• 金额: $ 3.91万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10750246
• 关键词: 3-Dimensional; Acute; Agonist; Arterial Disorder; Arteries; Blood Vessels; Blood capillaries; Brain; Capillary Endothelial Cell; Cells; Cephalic; Cerebral small vessel disease; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Chronic; Complex; Computer software; DTR gene; Data; Dementia; Deposition; Diameter; Disease; Distal; Endothelial Cells; Epidermal Growth Factor Receptor; Exposure to; Extracellular Domain; Functional disorder; Genetic; Glyburide; Goals; Hour; Hyperactivity; Image; Immunohistochemistry; Impairment; Induced Mutation; Ischemic Stroke; Kinetics; Ligands; Link; Literature; Location; Matrix Metalloproteinase Inhibitor; Measures; Membrane Potentials; Metabolic; Metabolic Diseases; Microcirculation; Microvascular Dysfunction; Modality; Modeling; Morphology; Mus; Mutation; NOTCH3 gene; Nature; Neurons; Nutrient; Paper; Patients; Perfusion; Pericytes; Physiological; Pinacidil; Population; Potassium; Preparation; Production; Property; Proteins; Publishing; Reagent; Receptor Aggregation; Receptor Inhibition; Receptor Signaling; Regulation; Relaxation; Reporting; Role; Sentinel; Signal Transduction; Smooth Muscle Myocytes; Subcortical Infarctions; Subcortical Leukoencephalopathy; Syndrome; TIMP3 gene; Techniques; Testing; Thinness; Training; Vascular Dementia; Vascular Smooth Muscle; Vasodilation; antagonist; arteriole; autosome; cell type; comparison control; electrical property; experimental study; extracellular; genetic approach; in vivo; insight; knock-down; mouse model; mutant; neurovascular; neurovascular coupling; new therapeutic target; novel; parenchymal arterioles; patch clamp; receptor; response; two-photon; uK-ATP-1 potassium channel

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.

项目总结