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

基本信息

  • 批准号:
    10606485
  • 负责人:
  • 金额:
    $ 56.41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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:
  • 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
  • 通讯作者:
    V. Omojola;Zaria Hardnett;Hannah W. Song;Hai Dong;D. J. Alexander;Adeola O Adebayo Michael;R. Gleason;M. Platt
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Edward A. Botchwey其他文献

Edward A. Botchwey的其他文献

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{{ truncateString('Edward A. Botchwey', 18)}}的其他基金

T32 CTEng (Cellular and Tissue Engineering) Training Program
T32 CTEng(细胞和组织工程)培训计划
  • 批准号:
    10641891
  • 财政年份:
    2022
  • 资助金额:
    $ 56.41万
  • 项目类别:
T32 CTEng (Cellular and Tissue Engineering) Training Program
T32 CTEng(细胞和组织工程)培训计划
  • 批准号:
    10420388
  • 财政年份:
    2022
  • 资助金额:
    $ 56.41万
  • 项目类别:
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
  • 财政年份:
    2021
  • 资助金额:
    $ 56.41万
  • 项目类别:
Regenerative Immunotherapy using light triggered in vivo activation of adhesive peptides
使用光触发体内粘附肽激活的再生免疫疗法
  • 批准号:
    10252435
  • 财政年份:
    2020
  • 资助金额:
    $ 56.41万
  • 项目类别:
Immune Modulatory Nanofibers for Skeletal Muscle Reconstruction
用于骨骼肌重建的免疫调节纳米纤维
  • 批准号:
    9565183
  • 财政年份:
    2017
  • 资助金额:
    $ 56.41万
  • 项目类别:
2015 Biomaterials & Tissue Engineering Gordon Research Conference and Gordon Research Seminar
2015年生物材料
  • 批准号:
    8986494
  • 财政年份:
    2015
  • 资助金额:
    $ 56.41万
  • 项目类别:
Therapeutic S1P Drug Targets for Cranial Bone Repair
颅骨修复的治疗性 S1P 药物靶点
  • 批准号:
    8069853
  • 财政年份:
    2009
  • 资助金额:
    $ 56.41万
  • 项目类别:
Therapeutic S1P Drug Targets for Cranial Bone Repair
颅骨修复的治疗性 S1P 药物靶点
  • 批准号:
    8543695
  • 财政年份:
    2009
  • 资助金额:
    $ 56.41万
  • 项目类别:
Phospholipid Growth Factors for Therapeutic Arteriogenesis and Tissue Engineering
用于治疗性动脉生成和组织工程的磷脂生长因子
  • 批准号:
    8895064
  • 财政年份:
    2009
  • 资助金额:
    $ 56.41万
  • 项目类别:
Therapeutic S1P Drug Targets for Cranial Bone Repair
颅骨修复的治疗性 S1P 药物靶点
  • 批准号:
    7858504
  • 财政年份:
    2009
  • 资助金额:
    $ 56.41万
  • 项目类别:

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