Artery biomechanics and vascular damage in sickle cell disease

在美国，镰状细胞病(SCD)影响着大约10万人，但30万婴儿出生时就患有 全球每年的SCD。目前，作为一种治疗方法的药物选择很少，而且预期寿命 对这些人来说仍然很低。动脉加速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期间，出血性中风的风险增加。弹性薄板 在SCD的儿童尸检标本中发现了碎裂的特征，但潜在的机制 目前尚不清楚，因此无法预防。半胱氨酸组织蛋白是与弹性蛋白有关的强大的蛋白水解酶 和心血管疾病(即动脉粥样硬化)中的胶原降解。它是最近由私人侦探出版的 在转基因镰状细胞小鼠模型中，组织蛋白具有类似的活性，并抑制JNK信号转导 阻断了这一点以及病理动脉重塑和生物力学后果。长期目标 是确定新的治疗靶点，以抑制蛋白分解活性和导致 儿童和成人动脉弹性蛋白和胶原加速降解及病理生物力学研究 使用SCD，并确定随着时间的推移累积的伤害。目的是研究组织蛋白酶介导的 SCD引起的大动脉病变和病理生物力学改变造成不可修复的损害， 如果根治性的骨髓疗法能防止动脉进一步重塑。根据初步数据和 已发表的研究中，中心假说是组织蛋白酶介导的弹性蛋白溶解和胶原溶解活性在 大动脉是jnk依赖和下游引起的慢性炎症(肿瘤坏死因子α和单核细胞增多症)。 由镰状细胞病引起。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，弹性膜中组织蛋白酶K的表达和胶原的SCD降解，并积累损伤 使用由研究人员产生的一种新的小鼠模型的动脉，该模型是转基因的镰状细胞 疾病，但对组织蛋白酶K无效。目的2.改进下调组织蛋白酶的JNK抑制策略 表达并保护动脉的完整性。目的3.确定根治性骨髓移植在预防进一步 动脉损伤，以及进一步药物干预的必要性。这项工作意义重大，因为它 成功将确定保存动脉完整性的机制，这些动脉在 终生患有SCD，即使在治愈的骨髓移植后也是如此。创新之处包括：1)研究动脉 SCD的重塑并发症与脱氧的毛细血管后小静脉和微循环相反 这在该领域占据主导地位；2)从弹性蛋白碎裂中分解胶原降解并影响 SCD中的动脉力学；3)确定维持血管完整性可能提供的关键年龄 提高了预防未来心脑血管并发症、影响质量和 患有遗传性疾病的镰状细胞病患者的生命周期。

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.