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TACE and Clock mechanisms in aging and vascular stiffening

衰老和血管硬化中的 TACE 和时钟机制

基本信息

批准号：
9553438
负责人：
Zsolt Bagi
金额：
$ 44.87万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9553438
关键词：
ARNTL gene Age Aging Aging-Related Process Arteries Blood Blood Vessels Cardiovascular Diseases Cause of Death Cessation of life Chronology Circadian Rhythms Collagen Complex Data Development Dilator Disintegrins Elasticity Elastin Elderly Enzymes Exhibits Functional disorder Gene Expression Gene Proteins Genes Genetic Genetic Transcription Goals Health Heart Diseases Human Hypertrophy IL6 gene Impairment Knock-out Knockout Mice Life Link Longevity Measures Mediating Mediator of activation protein Metalloproteases Modeling Molecular Mus Myocardial Infarction Organ Organ failure Outcomes Research Output Pathologic Patients Peripheral Population Preparation Property Regulation Relaxation Reporter Research Rodent Signal Transduction Sleep Speed Stroke Structural defect TNF gene Testing Time Transplantation Up-Regulation Variant Vascular Diseases Vascular remodeling age effect age related aged arterial remodeling arterial stiffness base blood vessel transplantation circadian pacemaker clinically relevant cost cytokine disability in vivo indexing insight man mechanotransduction mouse model novel protein expression skills translational approach vascular abnormality

项目摘要

PROJECT SUMMARY Cardiovascular disease remains one of the leading causes of death in the world. Its progression is part of the aging process. From mouse to man, one consistent feature of aging and cardiovascular disease is the stiffening of blood vessels. This elastic property is tantamount to blood vessels to effectively deliver blood to target organs. With progressive stiffening, the consequence can be organ failure and death often as a consequence of heart attacks and strokes, which exhibit a unique timing, a circadian rhythm. Indeed, the molecular components of circadian rhythm—the circadian clock, including Bmal1, Clock, Per, and Cry, which we have shown are expressed and oscillating in blood vessels are intimately connected with the aging of blood vessels. In mice with circadian dysfunction (Bmal1-KO mice), we have discovered that there is increased vascular stiffness in their blood vessels, suggesting that a broken clock may speed the aging of blood vessels, and age-dependent worsening of pathological vascular remodeling. We have also found that the disintegrin/metalloprotease ADAM17/TACE tracks uniquely with age in human blood vessels, and that it exhibits a circadian rhythm as do its outputs including JAM-1/F11r, TNF, and IL6r. Moreover, we also demonstrate that Bmal1-KO mice exhibit increased levels of the cytokine outputs TNF and IL6, and in a microarray study find Bmal1-KO naïve and transplanted vessels exhibit significant changes in ADAM17 targets. The central hypothesis of this application is that dysfunction of circadian clock is a prime mediator of age-related impairment of arterial relaxation and elasticity, which we propose is through ADAM17 regulation. Three Specific Aims are proposed. In Specific Aim 1 we will determine if a dysfunctional circadian clock mediates accelerated vascular dysfunction and arterial stiffening in aging. In Specific Aim 2, we will dissect the arterial wall-intrinsic and extrinsic mechanisms, which alter vascular clock and cause arterial stiffness in aging. In Specific Aim 3, we propose to examine the relationship between circadian clock dysfunction and ADAM17 activation in age-dependent vascular stiffening.

项目总结心血管疾病仍然是世界上主要的死亡原因之一。它的进步是老化过程。从老鼠到人，衰老和心血管疾病的一个始终如一的特征是僵硬血管的数量。这种弹性特性相当于血管有效地将血液输送到靶器官。随着进行性僵硬，其后果可能是器官衰竭和死亡，通常是心脏的结果。攻击和中风，表现出独特的时机，一种昼夜节律。事实上，它的分子组成昼夜节律-生物钟，包括BMal1、Clock、Per和Cry，我们已经展示了在血管中的表达和振荡与血管的衰老密切相关。在小鼠身上对于昼夜节律紊乱的小鼠(BMal1-KO小鼠)，我们发现在他们的血管，这表明时钟坏了可能会加速血管的衰老，并且与年龄有关病理性血管重塑加重。我们还发现去整合素/金属蛋白酶 ADAM17/TACE独特地跟踪人类血管的年龄，并显示出昼夜节律其输出包括JAM-1/F11R、肿瘤坏死因子和白介素6R。此外，我们还证明了BMal1-KO小鼠表现出细胞因子水平增加，产生肿瘤坏死因子和白介素6，在微阵列研究中发现BMal1-KO幼稚和移植血管的ADAM17靶点有明显变化。这个应用程序的中心假设生物钟功能障碍是与年龄相关的动脉松弛和功能损害的主要介质弹性，我们建议通过ADAM17监管。提出了三个具体目标。以特定的目标我们将确定生物钟失调是否会导致加速的血管功能障碍和动脉衰老时变得僵硬。在特定的目标2中，我们将剖析动脉壁的内在和外在机制，这是在衰老过程中改变血管时钟，导致动脉僵硬。在具体目标3中，我们建议研究年龄依赖性血管硬化中生物钟功能障碍与ADAM17激活的关系。