Artery biomechanics and vascular damage in sickle cell disease

镰状细胞病（SCD）影响美国约10万人，但30万婴儿出生时患有 在全球范围内每年都有SCD。目前，很少有药物选择可作为治疗， 仍然很低。加速动脉损伤的后果包括风险增加221倍 儿童中风的风险增加，然后在生命的第三个十年中出血性中风的风险增加。弹性膜 碎片化是SCD患儿尸检标本的标志，但其潜在机制 是不明确的，因此无法预防。半胱氨酸组织蛋白酶是与弹性蛋白有关的强有力的蛋白酶 以及心血管疾病（即动脉粥样硬化）中的胶原降解。它最近由PI出版， 组织蛋白酶在转基因镰状细胞小鼠模型中具有类似的活性， 阻断了这一点以及病理性动脉重塑和生物力学后果。长期目标 是确定新的治疗靶点，以抑制蛋白水解活性和细胞机制， 儿童和成人动脉中弹性蛋白和胶原降解加速和病理生物力学 与SCD，并确定随着年龄的累积损害。目的是研究组织蛋白酶介导的 由于SCD引起的大动脉中的动脉病和病理生物力学变化导致不可修复的损伤， 以及治愈性骨髓治疗是否能阻止进一步的动脉重塑。根据初步数据和 已发表的研究中，中心假设是组织蛋白酶介导的弹性蛋白溶解和胶原溶解活性， 大动脉是JNK依赖性的，是慢性炎症（TNFα和单核细胞增多）的下游， 镰状细胞病这一假设将根据以下目标进行检验：目标1。确定角色 随着小鼠年龄的增长和损伤的积累， 研究人员使用一种新的镰状细胞转基因小鼠模型， 疾病，但组织蛋白酶K无效。目标2.改善下调组织蛋白酶的JNK抑制策略 表达和保护动脉完整性。目标3.为了确定治疗性BMT在预防进一步 动脉损伤，以及需要进一步的药物干预。这项工作意义重大，因为它 成功将确定机制，以保持动脉的完整性，经历了渐进性损害超过一个 即使在治愈性骨髓移植后，SCD的寿命也是如此。创新点包括：1）研究动脉 SCD的重塑并发症，而不是缺氧的毛细血管后微静脉和微循环 2）从弹性蛋白片段化和影响胶原蛋白降解来分解胶原蛋白， SCD中的动脉力学;以及3）确定维持血管完整性可能提供的关键年龄 提高预防未来心血管和脑血管并发症的机会，影响质量， 镰状细胞病遗传病患者的寿命。

Sickle cell disease (SCD) affects approximately 100,000 people in the U.S. but 300,000 babies are born with SCD every year globally. Currently few pharmaceutical options are available as a therapy, and life expectancy is still low for these individuals. Consequences of accelerated arterial damage include a 221-fold increased risk of strokes in children and then increased risk of hemorrhagic strokes during the third decade of life. Elastic lamina fragmentation were hallmarks identified in autopsy specimens of children with SCD, but underlying mechanisms are unclear and therefore cannot be prevented. Cysteine cathepsins are powerful proteases implicated in elastin and collagen degradation in cardiovascular disease (i.e. atherosclerosis). It was recently published by the PIs that cathepsins are similarly active in a transgenic sickle cell mouse model, and inhibition of JNK signaling blocked this as well as pathological arterial remodeling and biomechanical consequences. The long term goal is to identify novel therapeutic targets to inhibit proteolytic activity and cellular mechanisms that cause accelerated elastin and collagen degradation and pathological biomechanics in arteries of children and adults with SCD, and determine accumulated damage as they age. The objective is to investigate cathepsin-mediated arteriopathy and pathological biomechanical changes in large arteries due to SCD causing irreparable damage, and if curative bone marrow therapies prevent further arterial remodeling. Based on preliminary data and published studies, the central hypothesis is that cathepsin-mediated elastinolytic and collagenolytic activity in large arteries is JNK-dependent and downstream of the chronic inflammation (TNFα and monocytosis) caused by sickle cell disease. This hypothesis will be tested according to the following aims: Aim 1. To determine roles of cathepsin K in elastic lamina and collagen degradation by SCD as mice age and accumulate damage to arteries using a new mouse model that was generated by the investigators that is transgenic for sickle cell disease but null for cathepsin K. Aim 2. To improve JNK inhibition strategies that downregulate cathepsin expression and protect arterial integrity. Aim 3. To determine efficacy of curative BMT in preventing further arterial damage, and the need for further pharmaceutical interventions. This work is significant because its success will identify mechanisms to preserve integrity of arteries that undergo progressive damage over a lifetime with SCD even after curative bone marrow transplants. Innovative aspects include: 1) Studying arterial remodeling complications of SCD as opposed to the deoxygenated post-capillary venules and microcirculation that has dominated the field; 2) decomposing collagen degradation from elastin fragmentation and impact on arterial mechanics in SCD; and 3) identifying critical ages by which maintenance of vascular integrity may offer improved chance of preventing future cardiovascular and cerebrovascular complications, impacting quality and duration of life of those living with the genetic disorder sickle cell disease.