Artery biomechanics and vascular damage in sickle cell disease

镰状细胞病的动脉生物力学和血管损伤

• 批准号: 10606485
• 负责人: Edward A. Botchwey
• 金额: $ 56.41万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606485
• 关键词: 5 year old; Acceleration; Adult; Affect; African; Age; Age Months; Aging; Aneurysm; Angiography; Arterial Disorder; Arteries; Atherosclerosis; Autopsy; Biochemical; Biomechanics; Biomedical Engineering; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; Brain hemorrhage; Cardiovascular Diseases; Cardiovascular system; Carotid Arteries; Cathepsins; Cessation of life; Child; Chronic; Collagen; Cysteine; Data; Disease; Disease Progression; Elastases; Elasticity; Elastin; Endothelial Cells; Future; Genetic Diseases; Genetic Models; Genotype; Goals; Health; Hematological Disease; Hemorrhage; Heterozygote; Human; Individual; Inflammation; Inflammatory; Inherited; Injections; Internal carotid artery structure; Intervention; Ischemic Stroke; JUN gene; Knowledge; Life; Life Expectancy; Link; Liquid substance; MAPK8 gene; Magnetic Resonance; Maintenance; Mechanics; Mediating; Microcirculation; Mission; Modeling; Molecular; Monitor; Monocytosis; Morphology; Mus; Nanotechnology; Outcome; Paper; Pathologic; Pathology; Patients; Peptide Hydrolases; Peripheral Blood Mononuclear Cell; Persons; Pharmacologic Substance; Physiological; Proteins; Psyche structure; Public Health; Publishing; Quality of life; Regulation; Research; Research Personnel; Risk; Role; SP600125; Sickle Cell; Sickle Cell Anemia; Signal Pathway; Signal Transduction; Specimen; Stenosis; Stroke; Structure; TNF gene; Testing; Thinness; Transcription Factor AP-1; Transgenic Mice; Transgenic Organisms; United States; United States National Institutes of Health; Vascular Diseases; Wild Type Mouse; Work; age related; anterior cerebral artery; arterial remodeling; arterial stiffness; carboxypeptidase C; cathepsin K; cerebrovascular; collagenase; disability; efficacy evaluation; high risk; human disease; improved; inhibitor; innovation; middle cerebral artery; mouse model; nanoparticle; nanoparticle delivery; new therapeutic target; novel; novel therapeutics; pharmacologic; physically handicapped; postcapillary venule; predictive marker; preservation; prevent; racial minority; response; shear stress; stroke risk; success

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.

镰状细胞病（SCD）在美国影响约100,000人 SCD每年在全球范围内。目前，很少有药物选择作为治疗和预期寿命 这些人仍然很低。加速动脉损伤的后果包括风险增加221倍 在生命的第三个十年中，儿童中风，然后增加出血性中风的风险。弹性层 碎片化是SCD儿童的尸检标本中确定的标志，但基本机制 不清楚，因此无法预防。半胱氨酸组织蛋白酶是在弹性蛋白中实现的强大蛋白酶 心血管疾病（即动脉粥样硬化）中的胶原蛋白降解。它最近由PIS出版 在转基因镰状细胞小鼠模型中，组织蛋白酶同样活跃，并抑制JNK信号传导 阻止了这一点以及病理动脉的重塑和生物力学后果。长期目标 是确定新型的治疗靶标，以抑制引起的蛋白水解活性和细胞机制 儿童和成人动脉中的加速弹性蛋白和胶原蛋白降解和病理生物力学 随着年龄的增长，SCD并确定了加速损害。目的是研究组织蛋白酶介导的 由于SCD导致无法弥补的损害，大动脉的动脉病变和病理生物力学变化， 并且，如果治愈性骨髓疗法可防止进一步的动脉重塑。基于初步数据和 发表的研究中心假设是组织蛋白酶介导的弹性源源解释性和胶原式活性 大动脉是慢性感染的JNK依赖性和下游（TNFα和单核细胞增多）引起的 通过镰状细胞疾病。该假设将根据以下目的进行检验：目标1。 随着小鼠的年龄，弹性层中的组织蛋白酶K和胶原蛋白降解，并累积了损害 使用新的小鼠模型的动脉，该模型是由研究人员生成的，该模型是针对镰状细胞的转基因的 疾病，但无效组织蛋白酶K. AIM 2。改善JNK抑制策略，下调组织蛋白酶 表达和保护动脉完整性。目标3。确定治愈性BMT在防止进一步的效率 动脉损伤以及需要进一步的药物干预措施。这项工作很重要，因为它 成功将确定保持动脉完整性的机制，这些动脉在 即使在治愈骨髓移植后，SCD的寿命也是如此。创新方面包括：1）研究动脉 SCD的重塑并发症，而不是脱氧后毛细血管和微循环 这已经统治了领域； 2）分解弹性蛋白碎片的胶原蛋白降解和对 SCD中的动脉力学； 3）确定可以提供血管完整性维持的关键年龄 改善了预防未来心血管和脑血管并发症的机会，从而影响质量和 患有遗传疾病镰状细胞病的人的生命持续时间。

项目成果

Comparative analysis of arterial compliance in mice genetically null for cathepsins K, L, or S.

• DOI: 10.1016/j.jbiomech.2022.111266
• 发表时间: 2022-08
• 期刊: Journal of biomechanics
• 影响因子: 2.4
• 作者: V. Omojola;Zaria Hardnett;Hannah W. Song;Hai Dong;D. J. Alexander;Adeola O Adebayo Michael;R. Gleason;M. Platt