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.

在美国，大约有 100,000 人患有镰状细胞病 (SCD)，但有 300,000 名婴儿出生时患有镰状细胞病 目前全球每年都会出现 SCD 的治疗方法和预期寿命。 对于这些人来说，加速动脉损伤的后果仍然很低，其中风险增加了 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。 碎片是 SCD 儿童尸检标本中发现的标志，但其潜在机制 尚不清楚，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大蛋白酶。 心血管疾病（即动脉粥样硬化）中的胶原蛋白降解最近由 PI 发表。 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，并且抑制 JNK 信号传导 阻止这一现象以及病理性动脉重塑和生物力学后果是长期目标。 是确定新的治疗靶点来抑制蛋白水解活性和导致 儿童和成人动脉中弹性蛋白和胶原蛋白加速降解和病理生物力学 并确定随着年龄的增长而累积的损伤，目的是研究组织蛋白酶介导的。 SCD 引起的动脉病和大动脉病理性生物力学变化造成不可挽回的损害， 根据初步数据和，治愈性骨髓疗法是否可以防止进一步的动脉重塑。 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蛋白溶解活性 大动脉是 JNK 依赖性的，是慢性炎症（TNFα 和单核细胞增多症）引起的下游 该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累积损伤，弹性层中的组织蛋白酶 K 和 SCD 导致的胶原蛋白降解 使用研究人员创建的镰状细胞转基因新小鼠模型进行动脉研究 目标 2. 改善下调组织蛋白酶的 JNK 抑制策略 目标 3. 确定治疗性 BMT 在预防进一步发生方面的功效。 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。 成功将找到保护动脉完整性的机制，这些动脉在一段时间内会遭受渐进性损伤。 即使在治疗性骨髓移植后，SCD 患者的生命周期仍存在创新性的方面包括： 1) 研究动脉。 与毛细血管后微静脉脱氧和微循环相比，SCD 的重塑并发症 2) 分解弹性蛋白碎片造成的胶原蛋白降解及其影响 SCD 中的动脉力学；3) 确定维持血管完整性的关键年龄 提高预防未来心脑血管并发症的机会，影响质量和 镰状细胞病遗传性疾病患者的生命周期。

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