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.
项目总结/摘要 包括镰状细胞病(SCD)在内的溶血综合征是一种破坏性疾病, 在美国有10万人。这些患者中的每一个都患有广泛的心肺功能障碍, 红细胞溶血、高血浆细胞水平、高胰岛素血症、高 游离血红蛋白(Hb)、内皮细胞功能障碍和组织缺氧。肺血管疾病 肺动脉高压的形式,是显着增加,在这一人群中,没有任何适当的 治疗方案。本赠款申请和项目集中在阐明机制的非- 巨噬细胞活化的基础及其对SCD PH进展的贡献。 我们的数据显示,一个独特的巨噬细胞(M β)表型发生在两个死亡的成人SCD患者, 与PH以及SCD PH的啮齿动物模型不相关。 Hb的模拟,HO-1的表达,以及促有丝分裂、炎症和血管收缩介质, 缺氧(HX)诱导的PH也与SCD有关。此外,与缺氧驱动的PH一样,SCD患者 肺巨噬细胞聚集在重塑的前毛细血管周围的肺外膜区域 肺小动脉显示丛状病变和小肺小动脉再通。的 啮齿类动物模型和患有PH的人类SCD之间的表型相似性表明, 对Hb和HX同时暴露的免疫反应。此外,通过消除循环 在第5组PH的大鼠模型中,对Hb和低压HX的联合反应在- 在大鼠中减弱,表明在SCD PH的恶化中,m β s起着关键作用。 持续的缺氧诱导红细胞镰状化是一个关键过程, 受损红细胞的M β清除导致M β铁积累,M β铁稳态丧失 和进行性SCD-PH。我们进一步假设,受损的铁稳态促进了- 细胞外氧化,并暴露局部肺血管微环境, 铁介导的氧化和加速肺外周血管重塑。为了验证这个假设- 我们提出以下具体目标。 目的1将确定循环中高铁含量的单核细胞如何代谢重编程 在不同严重程度的SCD患者中。目的2在体内和体外将确定的贡献, 目的3将测试载铁的M β有助于SCD的机制;目的3将测试反式- 铁蛋白、膜铁转运蛋白抑制剂和铁螯合剂单独或组合作为治疗干预, 停止向SCD PH捐款。 深入了解这些关系将使我们能够确定新的治疗靶点, 肺动脉高压伴SCD。

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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