TACE and Clock mechanisms in aging and vascular stiffening

衰老和血管硬化中的 TACE 和时钟机制

• 批准号: 9219957
• 负责人: Zsolt Bagi
• 金额: $ 44.87万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 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/9219957
• 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; Light; 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

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.

项目摘要 心血管疾病仍然是世界上主要的死亡原因之一。它的发展是 衰老过程。从老鼠到人，衰老和心血管疾病的一个一致特征是僵硬 血管。这种弹性特性与血管有效地向靶器官传递血液。 随着渐进式僵硬，后果可能是器官衰竭和死亡，通常是由于心脏而导致的 攻击和中风，表现出独特的时机，昼夜节律。确实，分子成分 昼夜节律 - 昼夜节律，包括BMAL1，时钟，Per和Cry，我们显示的是 在血管中表达并振荡与血管衰老密切相关。在老鼠中 随着昼夜节律功能障碍（BMAL1-KO小鼠），我们发现血管刚度增加 他们的血管，表明折断的时钟可能会加快血管的衰老，并依赖年龄 病理血管重塑的恶化。我们还发现崩解蛋白/金属蛋白酶 ADAM17/TACE随着人类血管的年龄而独特地跟踪，并且表现出昼夜节律 它的输出包括JAM-1/F11R，TNF和IL6R。此外，我们还证明了BMAL1-KO小鼠展示 细胞因子输出水平升高TNF和IL6，在微阵列研究中发现BMAL1-KO幼稚，并且 移植的血管暴露了ADAM17靶标的显着变化。该应用的中心假设 是昼夜节律的功能障碍是与年龄相关的动脉放松和 我们提出的弹性是通过ADAM17调节。提出了三个具体目标。在特定目标中 1我们将确定功能失调的昼夜节律是否介导加速的血管功能障碍和动脉 衰老僵硬。在特定的目标2中，我们将剖析动脉壁内在和外部机制，这些机制 改变血管时钟并导致衰老中的动脉僵硬。在特定目标3中，我们建议检查 昼夜节律时钟功能障碍与ADAM17激活年龄依赖性血管僵硬之间的关系。