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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos 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

项目摘要

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氏病（AD）是一种普遍的疾病，对基本机制几乎没有理解疾病发展的背后。舒张功能障碍已被证明是独立的危险因素为了发展认知障碍。患有舒张期心力衰竭（DHF）和AD的患者代表高度需要热选择的人口，但不幸的是，治疗率最低由于对这两种疾病的了解不足，因此选择。血管功能障碍与DHF有关广告。由于慢性炎症状态，可能发生血管内皮功能障碍，驱动DHF/AD 病理。但是关于有助于认知的血管内皮机制知之甚少损害。特别是，腺苷激酶（ADK）在调节血流下起重要作用低氧条件主要通过其受体（A1R，A2A/A2BR和A3R）。从病理上讲，增加的ADK是在神经退行性疾病中实施，但其在DHF/AD的血管贡献中的作用病理是未知的。那我假设增强的ADK活动会损害，而ADK 抑制作用恢复，大脑实质小动物血管扩张剂功能，减轻DHF诱导的认知能力下降和与广告相关的病理结果的恶化。这个项目的目标是检查腺苷激酶在混合DHF和AD病理学中的血管扩张仪功能中的作用，并进一步阐明内皮ADK在血管反应性中的基本机制。我将通过以下内容进行研究两个具体的目标。 AIM 1。检验假设的假设，即增加脑血管ADK活性会损害血管扩张剂实质性动作的功能，令人担忧的混合DHF/AD病理学的认知功能障碍。目标2。测试 ADK还原的脑血管内皮选择缺失的假设和机制混合DHF/AD中的小副群artioles的血管扩张函数。通过这些目标，我将能够更好地阐明混合DHF和AD病理中的潜在血管贡献以及机械探测ADK在微血管功能障碍和最终认知障碍中的作用。