Vasculotide promotes cognitive improvement in rats with vascular dementia

Vasculotide 促进血管性痴呆大鼠的认知改善

• 批准号: 10605198
• 负责人: MICHAEL CHOPP
• 金额: $ 37.63万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605198
• 关键词: ANGPT1 gene; ATP-Binding Cassette Transporters; Affect; Alzheimer' s Disease; Anti-Inflammatory Agents; Antiinflammatory Effect; Attenuated; Automobile Driving; Axon; Biological Process; Blood - brain barrier anatomy; Blood Vessels; Brain; Caregivers; Cerebrospinal Fluid; Cerebrovascular Circulation; Cerebrum; Circulation; Clinical; Cognitive; Cognitive deficits; Data; Dementia; Demyelinations; Diffuse; Disease; Dose; Elderly; Event; Extravasation; Female; Gene Expression; Gene Expression Regulation; Genes; Health Personnel; Hippocampus; Hour; Hypoxia; IL6 gene; Impaired cognition; In Vitro; Infarction; Inflammation; Inflammatory Response; Injury; Interleukin-6; Investigation; Mediating; MicroRNAs; Modeling; Molecular; Neurologic; Neurons; Neurotoxins; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmacological Treatment; Rattus; Reporting; Rodent; Role; Safety; Series; Signal Pathway; Stroke; Synaptic plasticity; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Therapeutic Intervention; Transient Ischemic Attack; Vascular Dementia; Vascular Diseases; Vascular remodeling; Ventricular; Woman; aging population; angiogenesis; aquaporin 4; axon injury; blood-brain barrier disruption; brain tissue; cell injury; clinically relevant; cognitive recovery; diabetic rat; differential expression; frontal lobe; functional outcomes; glymphatic dysfunction; glymphatic function; glymphatic system; improved; longitudinal design; male; men; middle age; neuroinflammation; novel; novel therapeutic intervention; peptidomimetics; post stroke; potential biomarker; response; therapeutic evaluation; therapeutic target; tissue repair; wasting; water channel; white matter; white matter damage; white matter injury

ABSTRACT Vascular dementia (VaD) is common in patients after a stroke or after a series of mini-strokes and results from several mechanisms, one of which involves injury to blood vessels supplying deep white matter (WM) of the brain resulting in silent, multifocal, brain microinfarcts, vascular dysfunction, decrease in cerebral blood flow, and cerebral parenchymal cell damage. Extensive WM damage such as vacuolization, rarefaction, and demyelination in the periventricular region have been reported in patients with VaD. There is a critical need to develop therapeutic strategies for VaD that identify and target key pathophysiological events driving axonal/WM damage and cognitive deficits. The therapeutic effects of Vasculotide, an Angiopoietin-1 mimetic peptide, in VaD have not been investigated. Our preliminary in-vitro studies show that Vasculotide treatment can dose dependently increase axonal outgrowth in primary cortical neurons (PCN). In male retired breeder rats subjected to a multiple microinfarction (MMI) model of VaD, Vasculotide treatment initiated at 24 hours after MMI, significantly decreases axonal/WM injury and improves long term cognitive outcome. In a novel and clinically relevant approach, based on our robust preliminary data, we propose to use Vasculotide for the treatment of MMI induced VaD in male and female middle-aged rats (10-12 months old). We seek to develop Vasculotide as a therapeutic agent to decrease vascular dysfunction and axonal/WM injury, decrease inflammatory responses, attenuate glymphatic dysfunction and improve cognitive outcome. By affecting gene regulation, microRNAs (miRs) are involved in most biological processes and act as molecular rheostats that fine-tune and switch regulatory circuits governing tissue repair, inflammation, hypoxia-response, and angiogenesis. Elucidation of the role of miRs in VaD pathogenesis, and identification of key miRs that can potentially serve as therapeutic targets in VaD are lacking. We hypothesize that Vasculotide treatment induced vascular and axonal/WM remodeling; anti-inflammatory responses and cognitive recovery are mediated via modulation of key miRs and their target gene expression. Therefore, we propose three highly integrated and longitudinally designed Specific Aims. In Aim 1, we will perform dose-response studies and investigate the safety and long term cognitive outcome of Vasculotide treatment in middle-aged, male and female rats subject to MMI model of VaD. In Aim 2, we will investigate the therapeutic effects of Vasculotide on vascular remodeling, axonal/WM remodeling, synaptic plasticity, inflammatory responses and glymphatic waste clearance pathway in middle-aged rats subject to MMI. In Aim 3, using “gain or loss” of brain miR-145 and miR-124, we will test whether Vasculotide treatment induced therapeutic effects after MMI in rats are mediated via the miR-124/Interleukin-6 and miR-145/Aquaporin-4/ATP-binding cassette transporter A1 (ABCA1) signaling pathways. The long-term objective of this R01 application is to develop a novel treatment for VaD.

摘要 血管性痴呆(VAD)常见于中风后或一系列微小中风后的患者，其结果是 几种机制，其中之一涉及损伤供应大脑深白质(WM)的血管 大脑导致沉默，多灶性，脑微梗塞，血管功能障碍，脑血流量减少， 和脑实质细胞损伤。广泛的WM损害，如空泡化、稀疏化和 VaD患者的脑室周围区域有脱髓鞘的报道。迫切需要 制定VaD的治疗策略，识别并针对关键的病理生理事件驱动 轴突/WM损伤和认知缺陷。血管生成素-1类似物血管生成素的治疗作用 多肽，在vad中还没有被研究过。我们的初步体外研究表明，血管生成素治疗 可剂量依赖性地增加原代皮质神经元(PCN)的轴突生长。在退休的雄性繁殖者中 大鼠建立VaD多发微梗(MMI)模型，24小时开始给予血管紧张素转换酶 MMI后，显著减少轴突/WM损伤，改善长期认知结果。在一部小说中 临床上相关的方法，基于我们稳健的初步数据，我们建议使用血管紧张素治疗 MMI对10~12月龄雄性和雌性中年大鼠VaD的治疗作用我们寻求发展 血管紧张素作为治疗药物减少血管功能障碍和轴突/WM损伤 炎症反应，减轻淋巴功能障碍，改善认知结果。通过影响基因 调控，microRNAs(MiRs)参与大多数生物过程，并作为分子变阻器 微调和切换调控组织修复、炎症、缺氧反应和 血管生成。阐明miRs在vaD发病机制中的作用，并鉴定能够 在VAD中缺乏潜在的治疗靶点。我们假设血管紧张素治疗导致 血管和轴突/WM重塑；抗炎反应和认知恢复是通过 关键miRs及其靶基因表达的调控。因此，我们提出了三个高度整合的和 纵向设计的具体目标。在目标1中，我们将进行剂量反应研究，并调查 血管紧张素治疗中年、雌雄大鼠的安全性和长期认知结局 VAD的人机界面模型。在目标2中，我们将研究血管紧张素对血管的治疗作用。 重塑、轴突/WM重塑、突触可塑性、炎症反应和淋巴废物 MMI中年大鼠的清除途径。在目标3中，使用大脑miR-145和 MIR-124，我们将测试血管紧张素治疗是否对大鼠MMI后的治疗产生影响 通过miR-124/IL-6和miR-145/Aquaporin-4/ATP结合盒转运体A1(ABCA1) 信号通路。这种R01应用的长期目标是开发一种治疗VaD的新方法。

项目成果

Early therapeutic effects of an Angiopoietin-1 mimetic peptide in middle-aged rats with vascular dementia.

• DOI: 10.3389/fnagi.2023.1180913
• 发表时间: 2023
• 期刊: Frontiers in aging neuroscience
• 影响因子: 4.8

Treatment With an Angiopoietin-1 Mimetic Peptide Improves Cognitive Outcome in Rats With Vascular Dementia.

• DOI: 10.3389/fncel.2022.869710
• 发表时间: 2022
• 期刊: FRONTIERS IN CELLULAR NEUROSCIENCE
• 影响因子: 5.3
• 作者: Culmone, Lauren;Powell, Brianna;Landschoot-Ward, Julie;Zacharek, Alex;Gao, Huanjia;Findeis, Elizabeth L.;Malik, Ayesha;Lu, Mei;Chopp, Michael;Venkat, Poornima
• 通讯作者: Venkat, Poornima