The paradoxical response to iron in pulmonary hypertension of sickle cell disease

镰状细胞病肺动脉高压对铁的矛盾反应

基本信息

  • 批准号:
    10340518
  • 负责人:
  • 金额:
    $ 71.11万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-02-01 至 2026-01-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ ABSTRACT Hemolytic syndromes including sickle cell disease (SCD) are devastating illnesses that affect over 100,000 people in the United States. Each of these patients suffers a broad spectrum of cardiopulmonary complications and exercise intolerance caused by red blood cell hemolysis, high plasma levels of cell free hemoglobin (Hb), endothelial cell dysfunction, and tissue hypoxia. Pulmonary vascular disease in the form of pulmonary hypertension, is significantly increased in this population, without any adequate treatment options. This grant application and projects herein focus on elucidating the mechanistic un- derpinnings of macrophage activation and their contribution to the progression of SCD PH. Our data shows a unique macrophage (Mϕ) phenotype occurs in both deceased adult SCD patients di- agnosed with PH as well rodent models of SCD PH. This phenotype is described by intracellular accu- mulation of Hb, expression of HO-1, and mitogenic, inflammatory and vasoconstrictor mediators that are also associated with hypoxia (HX) induced PH. Furthermore, like hypoxia driven PH, SCD patient lung macrophages accumulate in the pulmonary adventitial regions surrounding remodeled pre-capillary pulmonary arterioles that show plexiform lesions and re-canalization of small pulmonary arterioles. The phenotypic similarities between rodent models and human SCD with PH indicate a novel maladaptive immune response to concomitant bouts of Hb and HX exposure. Moreover, by knocking out circulating mϕs in a rat model of group 5 PH, the response to combined Hb and hypobaric HX was significantly at- tenuated in rats, suggesting a critical role for mϕs in the exacerbation of SCD PH. We hypotheses that persistent bouts of hypoxia-induced erythrocyte sickling are a critical process that drives Mϕ removal of damaged RBCs causing accumulation of Mϕ iron, loss of Mϕ iron homeostasis and progressive SCD-PH. We further hypothesize that impaired iron homeostasis facilitates in- tracellular oxidation and exposes the local pulmonary vascular micro-environments to labile iron mediated oxidation and accelerated lung peripheral vascular remodeling. To test this hypoth- esis we propose the following specific aims. Aim 1 will determine how circulating monocytes with a high iron content are metabolically reprogramed in patients with differing severity of SCD. Aim 2 in vivo and in vitro will determine the contribution and mechanism by which iron loaded Mϕ contribute to SCD; and Aim 3 will test the effectiveness of trans- ferrin, ferroportin inhibitor, and iron chelators alone or in combination as a therapeutic intervention to halt Mϕ contributions to SCD PH. An in-depth understanding of these relationships will allow us to identify new therapeutic targets to pulmonary hypertension concomitant with SCD.
项目摘要/摘要

项目成果

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Paul Werner Buehler其他文献

Paul Werner Buehler的其他文献

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{{ truncateString('Paul Werner Buehler', 18)}}的其他基金

Bioengineering a novel therapeutic protein complex to minimize the effects of medical device induced hemolysis
生物工程新型治疗性蛋白质复合物可最大程度地减少医疗设备引起的溶血的影响
  • 批准号:
    10542403
  • 财政年份:
    2022
  • 资助金额:
    $ 71.11万
  • 项目类别:
The paradoxical response to iron in pulmonary hypertension of sickle cell disease
镰状细胞病肺动脉高压对铁的矛盾反应
  • 批准号:
    10553099
  • 财政年份:
    2022
  • 资助金额:
    $ 71.11万
  • 项目类别:
Bioengineering a novel therapeutic protein complex to minimize the effects of medical device induced hemolysis
生物工程新型治疗性蛋白质复合物可最大程度地减少医疗设备引起的溶血的影响
  • 批准号:
    10380296
  • 财政年份:
    2022
  • 资助金额:
    $ 71.11万
  • 项目类别:
Engineering a novel biomaterial for oxygen transport applications
设计用于氧传输应用的新型生物材料
  • 批准号:
    10545751
  • 财政年份:
    2021
  • 资助金额:
    $ 71.11万
  • 项目类别:
Bioengineering a Dual Function Protein Construct to Detoxify Heme and Hemoglobin
生物工程双功能蛋白质结构以解毒血红素和血红蛋白
  • 批准号:
    10437908
  • 财政年份:
    2021
  • 资助金额:
    $ 71.11万
  • 项目类别:
Bioengineering a Dual Function Protein Construct to Detoxify Heme and Hemoglobin
生物工程双功能蛋白质结构以解毒血红素和血红蛋白
  • 批准号:
    10308814
  • 财政年份:
    2021
  • 资助金额:
    $ 71.11万
  • 项目类别:
Engineering a novel biomaterial for oxygen transport applications
设计用于氧传输应用的新型生物材料
  • 批准号:
    10322431
  • 财政年份:
    2021
  • 资助金额:
    $ 71.11万
  • 项目类别:
Bioengineering a Dual Function Protein Construct to Detoxify Heme and Hemoglobin
生物工程双功能蛋白质结构以解毒血红素和血红蛋白
  • 批准号:
    10663258
  • 财政年份:
    2021
  • 资助金额:
    $ 71.11万
  • 项目类别:
Aerosolized therapy for hemoglobin toxicity in the treatment of hemolytic diseases
溶血性疾病治疗中血红蛋白毒性的雾化治疗
  • 批准号:
    10374485
  • 财政年份:
    2021
  • 资助金额:
    $ 71.11万
  • 项目类别:
Aerosolized therapy for hemoglobin toxicity in the treatment of hemolytic diseases
溶血性疾病治疗中血红蛋白毒性的雾化治疗
  • 批准号:
    10531919
  • 财政年份:
    2021
  • 资助金额:
    $ 71.11万
  • 项目类别:

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