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: 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
• 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

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.

项目概要 心血管疾病仍然是世界上死亡的主要原因之一。它的进展是 老化过程。从老鼠到人类，衰老和心血管疾病的一个一致特征是身体僵硬 的血管。这种弹性特性就相当于血管能够有效地将血液输送到目标器官。 随着进行性僵硬，结果可能是器官衰竭，甚至因心脏衰竭而死亡。 攻击和中风，表现出独特的时间，昼夜节律。事实上，其分子成分 昼夜节律——生物钟，包括 Bmal1、Clock、Per 和 Cry，我们已经展示了它们 血管中的表达和振荡与血管的老化密切相关。在小鼠中 在昼夜节律功能障碍（Bmal1-KO 小鼠）中，我们发现血管僵硬度增加 他们的血管，表明时钟损坏可能会加速血管的老化，并且与年龄有关 病理性血管重塑恶化。我们还发现解整合素/金属蛋白酶 ADAM17/TACE 独特地跟踪人类血管的年龄，并且它表现出昼夜节律 其输出包括 JAM-1/F11r、TNF 和 IL6r。此外，我们还证明 Bmal1-KO 小鼠表现出 细胞因子输出 TNF 和 IL6 的水平增加，并且在微阵列研究中发现 Bmal1-KO naïve 和 移植血管的 ADAM17 靶点表现出显着变化。本申请的中心假设 生物钟功能障碍是与年龄相关的动脉舒张功能障碍的主要调节因素 弹性，我们建议通过 ADAM17 调节。提出了三个具体目标。特定目标 1 我们将确定生物钟功能失调是否会介导加速血管功能障碍和动脉粥样硬化 老化时变硬。在具体目标 2 中，我们将剖析动脉壁的内在和外在机制， 改变血管时钟并导致衰老时的动脉僵硬。在具体目标 3 中，我们建议审查 年龄依赖性血管硬化中生物钟功能障碍与 ADAM17 激活之间的关系。