The Role of Adenosine Kinase in Mixed Diastolic Heart Failure and Alzheimer Disease

腺苷激酶在混合性舒张性心力衰竭和阿尔茨海默病中的作用

• 批准号: 10679989
• 负责人: Katie Anne Fopiano
• 金额: $ 4.33万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679989
• 关键词: Acceleration; Address; Adenosine; Adenosine Kinase; Affect; Aldosterone; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-Protein Precursor; Anti-Inflammatory Agents; Astrocytes; Automobile Driving; Blood Vessels; Blood flow; Brain; Brain region; Cardiovascular Physiology; Cardiovascular system; Cell Culture Techniques; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrum; Chronic; Clinical; Clinical Research; Cognitive; Cognitive deficits; Complex; Data; Dementia; Dependovirus; Development; Diastolic heart failure; Disease; Endothelial Cells; Endothelium; Endothelium-Dependent Relaxing Factors; Exhibits; Functional disorder; Genetic; Goals; Human; Hypoxia; Impaired cognition; Impairment; Individual; Inflammation Mediators; Inflammatory; Infusion procedures; Ischemia; Laboratories; Lasers; Measures; Memory; Metabolism; Microglia; Microvascular Dysfunction; Molecular; Mouse Protein; Mus; Neurodegenerative Disorders; Neurons; Outcome; Pathologic; Pathology; Patients; Perfusion; Physiological; Play; Population; Process; Protein Precursors; Protocols documentation; Risk Factors; Rodent Model; Role; Sensory; Signal Pathway; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelium; Vasodilator Agents; Vasomotor; Vibrissae; adenosine monophosphate-adenosine; behavior test; cerebrovascular; cognitive function; dementia risk; experimental study; hypoperfusion; improved; in vivo; in vivo two-photon imaging; kinase inhibitor; knock-down; mouse model; mutant; neuropathology; neuroprotection; neurovascular; neurovascular coupling; novel; parenchymal arterioles; pharmacologic; pressure; receptor; response; spatiotemporal; targeted treatment; vascular contributions; vascular endothelial dysfunction

PROJECT SUMMARY Alzheimer’s disease (AD) is a prevalent disease with little understanding into the underlying mechanisms behind the development of the disease. Diastolic dysfunction has been shown to be an independent risk factor for the development of cognitive impairment. Patients with both diastolic heart failure (dHF) and AD represent a population where therapeutic options are highly needed, but which unfortunately have minimal therapeutic options due to a poor understanding of both diseases. Vascular dysfunction has been implicated in dHF and AD. Due to a chronic inflammatory state, vascular endothelial dysfunction can occur, driving dHF/AD pathologies. But little is known regarding the vascular endothelial mechanisms that contribute to cognitive impairment. Specifically, adenosine kinase (ADK) plays an important role in regulating blood flow under hypoxic conditions largely via its receptors (A1R, A2A/A2BR, and A3R). Pathologically, increased ADK is implicated in neurodegenerative diseases, but its role in the vascular contributions underlying dHF/AD pathologies is unknown. Thus, I hypothesize that augmented ADK activity impairs, whereas ADK inhibition restores, cerebral parenchymal arteriole vasodilator function, mitigating the dHF-induced worsening of cognitive decline and AD-related pathological outcomes. The goal of this project is to examine the role of adenosine kinase in vasodilator function in a mixed dHF and AD pathology and to further elucidate the underlying mechanisms of endothelial ADK in vasoreactivity. I will study this through the following two Specific Aims. Aim 1. Test the hypothesis that increases in cerebrovascular ADK activity impair vasodilator function of parenchymal arterioles, worsening cognitive dysfunction in mixed dHF/AD pathologies. Aim 2. Test the hypothesis and mechanisms by which cerebrovascular endothelium-selective deletion of ADK restores vasodilator function of small parenchymal arterioles in mixed dHF/AD. Through these aims, I will be able to better elucidate the underlying vascular contribution in mixed dHF and AD pathologies as well as mechanistically probe for the role of ADK in microvascular dysfunction and eventual cognitive impairment.

项目摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种流行性疾病，其发病机制尚不清楚 疾病发展的背后。舒张功能障碍已被证明是一个独立的危险因素 导致认知障碍患有舒张性心力衰竭（dHF）和AD的患者代表 高度需要治疗选择，但不幸的是， 由于对这两种疾病的了解不多，血管功能障碍与dHF有关， AD.由于慢性炎症状态，可发生血管内皮功能障碍，导致dHF/AD 病理学。但是，关于血管内皮机制，有助于认知， 损伤具体地，腺苷激酶（ADK）在调节血液流动中起重要作用。 缺氧条件下，主要通过其受体（A1 R，A2 A/A2 BR和A3 R）。在病理学上，ADK增加是 与神经退行性疾病有关，但其在dHF/AD基础血管贡献中的作用 病理学是未知的。因此，我假设增强ADK活性损害，而ADK 抑制恢复脑实质小动脉血管扩张功能，减轻dHF诱导的 认知能力下降和AD相关病理结果恶化。该项目的目标是 检查腺苷激酶在混合dHF和AD病理学中血管舒张功能中的作用，并进一步 阐明内皮ADK在血管反应性中的潜在机制。我将通过以下几点来研究这一点 两个具体目标。目标1。验证脑血管ADK活性增加损害血管扩张剂的假设 实质小动脉的功能，在混合性dHF/AD病理中认知功能障碍恶化。目标二。测试 脑血管内皮细胞选择性ADK缺失恢复的假说和机制 混合型dHF/AD患者小实质小动脉的血管舒张功能。通过这些目标，我将能够 更好地阐明了混合dHF和AD病理学中潜在的血管作用， 机械地探索ADK在微血管功能障碍和最终的认知障碍中的作用。