Ectonucleotidase modulation of age-dependent vascular calcification and stiffness

外切核苷酸酶调节年龄依赖性血管钙化和僵硬度

基本信息

批准号：
10045790
负责人：
Nadia Razaq Sutton
金额：
$ 24.3万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10045790
关键词：
ADP Receptors ATP Receptors Achievement Adenosine Age Age-Years Aging Agonist Arteries Atherosclerosis Biological Process Biology of Aging Blood Vessels Brain C57BL/6 Mouse Calcium Cardiac Cardiovascular Diseases Cardiovascular system Cell surface Cells Cleaved cell Clinical Coagulation Process Collagen Coronary artery Cues Data Deposition Development Diagnostic radiologic examination Disease Elasticity Elastin Endothelial Cells Environment Enzymes Exposure to Extracellular Matrix Fibrosis Foundations Future Gene Expression Healthcare Heart Human Impairment Inflammation Inflammatory Kidney Knowledge Leukocytes Life Longevity Mediating Metabolic Mus Organ Osteogenesis Pathologic Patients Phenotype Physiologic pulse Physiological Play Population Process Production Proteins Proteomics Pulse Pressure Purinergic P1 Receptors Research Research Personnel Risk Factors Role Signal Transduction Smooth Muscle Myocytes Stress Stress Tests Surface Testing Time Vascular Diseases Vascular Smooth Muscle Vascular calcification age related aged calcification care burden coronary artery calcification demographics experimental study extracellular human tissue indexing inflammatory marker insight middle age mouse model osteogenic paracrine prevent stem transcription factor

项目摘要

Abstract With increasing age, blood vessels become stiffer and more calcified. In the latter years of the human lifespan, the process of vascular aging accelerates. The reason that blood vessels lose their youthful elasticity and ability to retard the deposition of calcium precipitously later in life is poorly understood. Ectonucleotidases are found on the surface of endothelial cells which line the inner surface of blood vessels, vascular smooth muscle cells, and leukocytes. The ectonucleotidase CD39 is responsible for cleaving ATP and ADP to form AMP, and subsequently, CD73 is responsible for generating adenosine from AMP. Since ATP and ADP are pro- inflammatory and act in a paracrine fashion, I hypothesize that ectonucleotidase activity plays a role in the vascular stiffness and calcification that occurs as a consequence of age. This is supported by my preliminary data in wild type (C57BL/6) mice, which demonstrates CD73 protein levels declined with age (up to 24 months) in the heart and kidney. This is also supported by preliminary data in mice and human tissues demonstrating that loss of CD73 expression promoted expression of the transcription factor Runx2, which is critical for osteogenesis. We hypothesize that loss of ectonucleotidase expression with age could have deleterious consequences on the vessel wall, resulting in an environment which promotes vascular calcification and stiffness. Since the role of ectonucleotidases in vascular aging is unknown, we will elucidate mechanisms which mediate age-dependent vascular calcification through the following aims. Aim 1: We will determine how age-dependent decline in vascular ectonucleotidase expression renders vessels susceptible to vascular calcification and fibrosis in a murine model. Aim 2: We will determine how ectonucleotidase activity mitigates arterial fibrosis and stiffness. Aim 3: We will determine if ectonucleotidase expression plays a role in age-driven human coronary artery calcification. Achievement of these aims will elucidate the role of ectonucleotidases in age-dependent vascular calcification and stiffness in mice and humans. The mechanistic insights obtained from these experiments will define my future investigative direction and serve as a foundation for a subsequent RO1 application as an independent investigator studying vascular biology and aging.

抽象的随着年龄的增长，血管变得更硬、更钙化。在人类生命的最后几年，血管老化的过程加速。血管失去年轻弹性的原因人们对生命后期急剧延缓钙沉积的能力知之甚少。核酸外切酶是存在于血管内表面的内皮细胞、血管平滑肌的表面细胞和白细胞。核酸外切酶 CD39 负责裂解 ATP 和 ADP 形成 AMP，并且随后，CD73 负责从 AMP 生成腺苷。由于 ATP 和 ADP 是亲炎症并以旁分泌方式起作用，我假设核酸外切酶活性在由于年龄而发生的血管僵硬和钙化。这是我的初步支持野生型 (C57BL/6) 小鼠的数据，表明 CD73 蛋白水平随着年龄的增长（最多 24 个月）而下降在心脏和肾脏。小鼠和人体组织的初步数据也支持了这一点 CD73 表达的缺失促进了转录因子 Runx2 的表达，这对于成骨。我们假设，随着年龄的增长，核酸外切酶表达的丧失可能会产生有害的影响。对血管壁产生影响，形成促进血管钙化的环境刚性。由于核酸外切酶在血管老化中的作用尚不清楚，我们将阐明其机制它通过以下目标介导年龄依赖性血管钙化。目标 1：我们将确定如何血管内切核苷酸酶表达的年龄依赖性下降使血管易受血管性小鼠模型中的钙化和纤维化。目标 2：我们将确定核酸外切酶活性如何减轻动脉纤维化和僵硬。目标 3：我们将确定核酸外切酶的表达是否在年龄驱动中发挥作用人体冠状动脉钙化。这些目标的实现将阐明核酸外切酶在小鼠和人类的年龄依赖性血管钙化和僵硬。获得的机制见解这些实验将确定我未来的研究方向，并为后续研究奠定基础 RO1申请作为独立研究者研究血管生物学和衰老。