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: 10390381
• 负责人: Edward A. Botchwey
• 金额: $ 58.09万
• 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/10390381
• 关键词: 5 year old; Address; 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; Elastin; Endothelial Cells; Future; Genetic Diseases; Genetic Models; Genotype; Goals; Health; Hematological Disease; Hemorrhage; Human; Individual; Inflammation; Inflammatory; Inherited; Injections; Internal carotid artery structure; Intervention; Ischemic Stroke; JUN gene; Knowledge; Lead; 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; Pharmacology; 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; 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; base; carboxypeptidase C; cathepsin K; cerebrovascular; collagenase; disability; high risk; human disease; improved; inhibitor; innovation; mouse model; nanoparticle; nanoparticle delivery; new therapeutic target; novel; novel therapeutics; 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）在美国影响了大约10万人，但有30万婴儿出生时就患有这种疾病