Complications of Hemolysis and Transfusion Therapy

溶血和输血治疗的并发症

基本信息

  • 批准号:
    10647721
  • 负责人:
  • 金额:
    $ 310.37万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-07-20 至 2025-06-30
  • 项目状态:
    未结题

项目摘要

Overall Abstract Our Program Project focuses on mechanistic understanding of the beneficial and harmful effects of red blood cell (RBC) transfusions in patients with hemoglobinopathies. Increasing evidence suggest that free hemoglobin and heme play central roles in many aspects of the pathophysiology of hemolytic anemias, especially in SCD, causing vascular endothelial dysfunction, inflammation, and oxidative stress. Our Team has shown that innate and key humoral immune cells and hematopoietic niche cells are sensitive to the effects hemolysis and that heme-sensing mechanisms are key to the response to transfusions. The overall working hypothesis of this PPG is that heme overload leads to altered immune system response and a dysregulated bone marrow niche. We further posit that effectiveness of transfusions in hemolytic disorders depends on their ability to switch the proinflammatory to an anti-inflammatory environment. Building on highly inter-related and synergistic research projects led by a group of multidisciplinary local experts, including a highly promising ESI, we will interrogate the impact of hemolysis and outcome of transfusions on complications associated with SCD, ranging from alloimmunization (Project 1) and infections of hemoparasites (Project 2) to ACS (Project 3) and potentially affecting hematopoietic transplant outcomes (Project 4). Specifically, we will probe heme pathways specifically in B and T cells during transfusions to test the hypothesis that hemolysis directly affects humoral immune response to transfusions and that altered DOCK8/ROS/HO-1 heme pathways dictate alloimmunization risk and even bystander hemolysis associated with life-threatening delayed hemolytic transfusion reactions (Project 1). We will examine mechanisms of bystander hemolysis in hemoparasite infections and test the hypothesis that the switch from anti- to proinflammatory states in response to hemolysis and exacerbation of dysregulated erythropoiesis may underlie the exaggerated hyperhemolytic state (Project 2). Building on our data on modulation of innate immune response by hemolysis, we will determine the relevance of heme-induced inflammatory macrophage in the development of the debilitating sickle acute chest syndrome and whether transfusion outcomes are dependent on an anti-inflammatory metabolic switch in macrophages (Project 3). We will also test the hypothesis that the proinflammatory effects of free heme leads to dysfunction of the bone marrow hematopoietic niche and hematopoietic stem/progenitor cells, which can be alleviated by transfusions (Project 4). An Administrative Core will facilitate communication and integrate scientific goals and assure that high scientific productivity standards are maintained. The Human Subject Core will provide clinically annotated biological samples as well as clinically based insights to facilitate and enhance the clinical applicability of the findings emerging from this Program Project. We believe that the proposed Projects are highly interactive and that advances developed within each will have great value to other Projects. We further believe that through a PPG mechanism our Program will achieve a comprehensive mechanistic understanding how transfusions impact key heme pathways in hemoglobinopathies will provide the necessary framework for optimization of transfusion management and support for these highly vulnerable patient population.
总体摘要 我们的计划项目侧重于机械性地理解红血的有益和有害影响 血红蛋白病患者的红细胞(RBC)输注。越来越多的证据表明,游离血红蛋白 和血红素在溶血性贫血的许多病理生理学方面发挥着中心作用,特别是在SCD中, 导致血管内皮细胞功能障碍、炎症和氧化应激。我们的团队已经证明了先天的 关键的体液免疫细胞和造血细胞对溶血和 血红素感应机制是输血反应的关键。这个PPG的总体工作假设 是血红素超载导致免疫系统反应改变和骨髓生态位失调。 我们进一步假设,输血治疗溶血性疾病的有效性取决于它们转换 从促炎到抗炎的环境。建立在高度相关和协同研究的基础上 由一群多学科的当地专家领导的项目,包括非常有希望的ESI,我们将审问 溶血和输血对SCD相关并发症的影响 同种异体免疫(项目1)和血寄生虫感染(项目2)到急性冠脉综合征(项目3)和可能 影响造血移植结果(项目4)。具体地说,我们将具体探索亚铁血红素的途径 输血时B和T细胞中的溶血直接影响体液免疫的假说 输血反应和DOCK8/ROS/HO-1血红素通路的改变决定了同种异体免疫的风险和 甚至旁观者的溶血也与危及生命的延迟溶血反应有关(项目1)。 我们将研究血寄生虫感染中旁观者溶血的机制,并检验以下假设 溶血和调节失调加重时从抗炎状态到促炎状态的转变 红细胞生成可能是夸大的高溶血状态的基础(项目2)。以我们的数据为基础 通过溶血调节先天免疫反应,我们将确定与血红素诱导的相关性 炎性巨噬细胞在衰弱镰刀型急性胸腔综合征发病中的作用 输血结果取决于巨噬细胞的抗炎代谢开关(项目3)。我们 还将检验游离态血红素的促炎作用会导致骨髓功能障碍的假设 造血龛和造血干/祖细胞,可通过输血缓解(项目 4)。行政核心将促进沟通,整合科学目标,并确保 保持科学的生产力标准。人类主体核心将提供临床注释 生物样本以及基于临床的见解,以促进和加强临床适用性 从该计划项目中得出的结果。我们相信,拟议的项目具有高度的互动性和 在每个项目中开发的进展将对其他项目具有极大的价值。我们进一步相信,通过一个 PPG机制我们的计划将实现对输血如何影响的全面机械性理解 血红蛋白疾病中的关键血红素途径将为优化输血提供必要的框架 对这些高度脆弱的患者群体的管理和支持。

项目成果

期刊论文数量(35)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Non-Transferrin-Bound Iron in the Spotlight: Novel Mechanistic Insights into the Vasculotoxic and Atherosclerotic Effect of Iron.
Prognostic factors associated with COVID-19 related severity in sickle cell disease.
  • DOI:
    10.1016/j.bcmd.2021.102627
  • 发表时间:
    2021-12
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Yurtsever N;Nandi V;Ziemba Y;Shi PA
  • 通讯作者:
    Shi PA
The novel GATA1-interacting protein HES6 is an essential transcriptional cofactor for human erythropoiesis.
  • DOI:
    10.1093/nar/gkad167
  • 发表时间:
    2023-06-09
  • 期刊:
  • 影响因子:
    14.9
  • 作者:
    Wang, Zi;Wang, Pan;Zhang, Jieying;Gong, Han;Zhang, Xuchao;Song, Jianhui;Nie, Ling;Peng, Yuanliang;Li, Yanan;Peng, Hongling;Cui, Yajuan;Li, Heng;Hu, Bin;Mi, Jun;Liang, Long;Liu, Hong;Zhang, Ji;Ye, Mao;Yazdanbakhsh, Karina;Mohandas, Narla;An, Xiuli;Han, Xu;Liu, Jing
  • 通讯作者:
    Liu, Jing
Sickle Cell Anemia and Babesia Infection.
  • DOI:
    10.3390/pathogens10111435
  • 发表时间:
    2021-11-04
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Beri D;Singh M;Rodriguez M;Yazdanbakhsh K;Lobo CA
  • 通讯作者:
    Lobo CA
Evidence for continued dose escalation of plerixafor for hematopoietic progenitor cell collections in sickle cell disease.
  • DOI:
    10.1016/j.bcmd.2021.102588
  • 发表时间:
    2021-09
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Boulad F;Zhang J;Yazdanbakhsh K;Sadelain M;Shi PA
  • 通讯作者:
    Shi PA
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Karina Yazdanbakhsh其他文献

Karina Yazdanbakhsh的其他文献

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{{ truncateString('Karina Yazdanbakhsh', 18)}}的其他基金

Immune Pathophysiology of Sickle Cell Disease
镰状细胞病的免疫病理生理学
  • 批准号:
    10353672
  • 财政年份:
    2022
  • 资助金额:
    $ 310.37万
  • 项目类别:
Immune Pathophysiology of Sickle Cell Disease
镰状细胞病的免疫病理生理学
  • 批准号:
    10579970
  • 财政年份:
    2022
  • 资助金额:
    $ 310.37万
  • 项目类别:
Admin Core
管理核心
  • 批准号:
    10456793
  • 财政年份:
    2020
  • 资助金额:
    $ 310.37万
  • 项目类别:
Complications of Hemolysis and Transfusion Therapy
溶血和输血治疗的并发症
  • 批准号:
    10220124
  • 财政年份:
    2020
  • 资助金额:
    $ 310.37万
  • 项目类别:
Admin Core
管理核心
  • 批准号:
    10647722
  • 财政年份:
    2020
  • 资助金额:
    $ 310.37万
  • 项目类别:
Alloimmunization and Humoral Response to Hemolysis
同种免疫和溶血的体液反应
  • 批准号:
    10220127
  • 财政年份:
    2020
  • 资助金额:
    $ 310.37万
  • 项目类别:
Complications of Hemolysis and Transfusion Therapy
溶血和输血治疗的并发症
  • 批准号:
    10023587
  • 财政年份:
    2020
  • 资助金额:
    $ 310.37万
  • 项目类别:
Complications of Hemolysis and Transfusion Therapy
溶血和输血治疗的并发症
  • 批准号:
    10456792
  • 财政年份:
    2020
  • 资助金额:
    $ 310.37万
  • 项目类别:
Alloimmunization and Humoral Response to Hemolysis
同种免疫和溶血的体液反应
  • 批准号:
    10647731
  • 财政年份:
    2020
  • 资助金额:
    $ 310.37万
  • 项目类别:
Alloimmunization and Humoral Response to Hemolysis
同种免疫和溶血的体液反应
  • 批准号:
    10456796
  • 财政年份:
    2020
  • 资助金额:
    $ 310.37万
  • 项目类别:

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