Mechanisms of Inflammation in Sickle Cell Disease

镰状细胞病的炎症机制

基本信息

  • 批准号:
    10604366
  • 负责人:
  • 金额:
    $ 55.04万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-04-01 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

Project Summary/Abstract Numerous studies show the mechanisms by which sickle cell disease (SCD) induces vasculopathy and increases vasocongestion are complex and multifactorial. In this revised, renewal application, we hypothesize that SCD induces vasculopathy as one of the first steps in the mechanism by which SCD increases vaso- occlusion. Our studies show that SCD induces a destructive cycle that is initiated by MPO and propagated by high mobility group box-1 (HMGB1), and one other inflammatory component that alters pulmonary physiology, impairs vascular function, and increases vasocongestion. Previously, we reported L-acetyl-lysyltyrosylcysteine amide (KYC) inhibits MPO, improves vascular function and reduces liver injury induced by excessive vasocongestion in SCD mice. New studies suggest that KYC not only reduces sickle RBC (sRBC) congestion but also increases the number of round sRBC in the lungs of SCD mice. Mechanistic studies reveal that KYC isn't just an inhibitor of MPO toxic oxidant production, but rather, is a unique tripeptide substrate that exploits MPO peroxidase activity to be converted into a novel anti-inflammatory agent that inactivates HMGB1 and activates the cellular pathways that are responsible for antioxidant defense enzyme expression in the lung. As KYC inhibits multiple inflammatory components in our hypothesized destructive cycle, and even activates a component that mediates antioxidant gene expression, new studies using mechanistic inhibitors are required for determine which components increase vasculopathy and vasocongestion in SCD. While a systems pharmaceutical agent may be useful for treating multifactorial diseases, they cannot be used to identify causal mechanisms directly. In this revised application, we hypothesize that SCD induces a destructive cycle, mediated by at least three major components. Our working hypothesis is SCD induces a destructive cycle that is composed of MPO, HMGB1 and a novel, dysregulate gene and together induce vasculopathy and increase vasocongestion. By treating sickle mice, sickle MPO knockout (ko) mice, chimeric sickle Tamoxifen- inducible HMGB1 ko mice and another chimeric sickle ko mice with highly selective mechanistic inhibitors we will be able to determine if and the extent to which MPO, HMGB1 and the third gene product, alone and/or in combination induces vasculopathy and increases vasocongestion. To assess vasculopathy, we will quantify differences in pulmonary artery relaxation, pulmonary permeability, sRBC vasocongestion, and susceptibility of each mouse strain to sRBC vasocongestion induced by hypoxia-reoxygenation injury (HRI) in Townes homozygote sickle Hb (SS) wt SS Mpo ko mice, and chimeric SS novel gene ko mice. Our long-term goals are to confirm the identities of each component and develop novel therapies aimed at improving vascular function and reducing sRBC vasocongestion.
项目总结/摘要 许多研究表明镰状细胞病(SCD)诱导血管病变的机制, 增加血管充血是复杂的和多因素的。在这份修订后的更新申请中,我们假设 SCD诱导血管病变是SCD增加血管病变机制的第一步, 闭塞我们的研究表明,SCD诱导了一个破坏性周期,该周期由MPO启动,并通过 高迁移率族蛋白-1(HMGB 1)和另一种改变肺生理学的炎症成分, 损害血管功能并增加血管充血。 以前,我们报道了L-乙酰赖氨酰酪氨酸半胱氨酸酰胺(KYC)抑制MPO,改善血管功能, 减少SCD小鼠中由过度血管充血引起的肝损伤。新的研究表明,KYC不仅 减少了镰状红细胞(sRBC)充血,但也增加了SCD小鼠肺中圆形sRBC的数量。 机制研究表明,KYC不仅是MPO毒性氧化剂产生的抑制剂,而且是一种独特的 利用MPO过氧化物酶活性转化为新型抗炎剂的三肽底物 使HMGB 1失活,并激活负责抗氧化防御酶的细胞通路 在肺部的表达。由于KYC抑制了我们假设的破坏性周期中的多种炎症成分, 甚至激活一种介导抗氧化基因表达的成分, 需要抑制剂来确定哪些组分增加SCD中的血管病变和血管充血。 虽然系统药剂可用于治疗多因素疾病,但它们不能用于治疗 直接识别因果机制。在这个修改后的申请中,我们假设SCD诱导了一种破坏性的 循环,由至少三个主要组成部分介导。我们的假设是SCD导致了一个破坏性的循环 它由MPO、HMGB 1和一种新的失调基因组成,共同诱导血管病变, 增加血管充血。通过治疗镰状小鼠、镰状MPO敲除(ko)小鼠、嵌合镰状他莫昔芬- 诱导型HMGB 1 KO小鼠和另一种具有高选择性机制抑制剂的嵌合镰状KO小鼠, 将能够确定MPO、HMGB 1和第三种基因产物单独和/或联合 组合诱导血管病变并增加血管充血。为了评估血管病变,我们将量化 肺动脉舒张、肺通透性、sRBC血管充血和 各品系小鼠对Townes缺氧-复氧损伤(HRI)诱导的sRBC血管充血的影响 纯合子镰状Hb(SS)wt SS Mpo ko小鼠和嵌合SS新基因ko小鼠。我们的长期目标是 确认每种成分的特性,并开发旨在改善血管功能的新疗法, 和减少sRBC血管充血。

项目成果

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Kirkwood Arthur Pritchard其他文献

Kirkwood Arthur Pritchard的其他文献

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{{ truncateString('Kirkwood Arthur Pritchard', 18)}}的其他基金

Mechanisms of Inflammation in Sickle Cell Disease
镰状细胞病的炎症机制
  • 批准号:
    10209615
  • 财政年份:
    2016
  • 资助金额:
    $ 55.04万
  • 项目类别:
Mechanisms of Inflammation in Sickle Cell Disease
镰状细胞病的炎症机制
  • 批准号:
    10380784
  • 财政年份:
    2016
  • 资助金额:
    $ 55.04万
  • 项目类别:
Biophysics of HDL Dysfunction
HDL 功能障碍的生物物理学
  • 批准号:
    8853934
  • 财政年份:
    2012
  • 资助金额:
    $ 55.04万
  • 项目类别:
Biophysics of HDL Dysfunction
HDL 功能障碍的生物物理学
  • 批准号:
    8620821
  • 财政年份:
    2012
  • 资助金额:
    $ 55.04万
  • 项目类别:
Biophysics of HDL Dysfunction
HDL 功能障碍的生物物理学
  • 批准号:
    8372143
  • 财政年份:
    2012
  • 资助金额:
    $ 55.04万
  • 项目类别:
Biophysics of HDL Dysfunction
HDL 功能障碍的生物物理学
  • 批准号:
    8511809
  • 财政年份:
    2012
  • 资助金额:
    $ 55.04万
  • 项目类别:
Novel Peptide MPO Inhibitors for Treating Atherosclerosis
治疗动脉粥样硬化的新型肽 MPO 抑制剂
  • 批准号:
    8046699
  • 财政年份:
    2011
  • 资助金额:
    $ 55.04万
  • 项目类别:
Novel Peptide MPO Inhibitors for Treating Atherosclerosis
治疗动脉粥样硬化的新型肽 MPO 抑制剂
  • 批准号:
    8208034
  • 财政年份:
    2011
  • 资助金额:
    $ 55.04万
  • 项目类别:
HDL Dysfunction and Vascular Inflammation
HDL 功能障碍和血管炎症
  • 批准号:
    7216745
  • 财政年份:
    2006
  • 资助金额:
    $ 55.04万
  • 项目类别:
HDL Dysfunction and Vascular Inflammation
HDL 功能障碍和血管炎症
  • 批准号:
    7392750
  • 财政年份:
    2006
  • 资助金额:
    $ 55.04万
  • 项目类别:

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  • 批准号:
    2140205
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  • 资助金额:
    $ 55.04万
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Collaborative Research: NSF-DFG: CAS: Electrochemical Hydrogenation of Amides and Esters
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  • 批准号:
    2140196
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    2022
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受阻酰胺的天体选择性合成-合成肽催化剂的探索-
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    504378162
  • 财政年份:
    2022
  • 资助金额:
    $ 55.04万
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    WBP Fellowship
Development of Peptide Chemical Modification Enabled by N-Halogenation of Amides
酰胺 N-卤化实现的肽化学修饰的发展
  • 批准号:
    22H02743
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职业:SusChEM:用于还原酰胺的铁催化剂
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  • 资助金额:
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Modulating Signaling Endocannabinoids and Fatty Acid Amides
调节信号传导内源性大麻素和脂肪酸酰胺
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镍催化仲酰胺的α-芳基化
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水中催化合成药用酰胺
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