TACE and Clock mechanisms in aging and 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。它的进展是 老化过程从老鼠到人，衰老和心血管疾病的一个一致特征是硬化， 的血管。这种弹性相当于血管将血液有效地输送到目标器官。 随着进行性硬化，后果可能是器官衰竭和死亡，通常是心脏病的后果。 发作和中风，表现出独特的时间，昼夜节律。事实上， 昼夜节律-生物钟，包括Bmal 1，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。小鼠 与昼夜节律功能障碍（Bmal 1-KO小鼠），我们已经发现，有增加的血管僵硬， 他们的血管，这表明一个破碎的时钟可能会加速血管的老化， 病理性血管重塑恶化。我们还发现去整合素/金属蛋白酶 ADAM 17/TACE在人类血管中独特地随年龄变化，并且它与其他血管疾病一样表现出昼夜节律。 其输出包括JAM-1/F11 r、TNF和IL 6 r。此外，我们还证明了Bmal 1-KO小鼠表现出 细胞因子输出TNF和IL 6水平增加，并且在微阵列研究中发现Bmal 1-KO幼稚， 移植血管在ADAM 17靶点上表现出显著变化。本申请的中心假设是 生物钟功能障碍是与年龄相关的动脉舒张受损的主要介质， 弹性，我们建议是通过ADAM 17调节。提出了三个具体目标。具体目标 1我们将确定功能失调的生物钟是否介导了加速的血管功能障碍和动脉粥样硬化。 在老化中硬化。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动脉硬化。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ADAM 17激活之间的关系

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.