Redor Pathways Regulating Nemeprotein Maturation in Asthma
Redor 通路调节哮喘中的 Neme 蛋白成熟
基本信息
- 批准号:9232190
- 负责人:
- 金额:$ 31.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2006
- 资助国家:美国
- 起止时间:2006-04-15 至
- 项目状态:未结题
- 来源:
- 关键词:AddressAdrenergic beta-AgonistsAgonistAirApoproteinsAsthmaBiological ModelsBronchoconstrictionBronchodilationBronchodilator AgentsCell Culture TechniquesCellsCharacteristicsCoculture TechniquesDataDefectDrug usageEnvironmentEnzymesEpithelialEpithelial CellsFDA approvedGlyceraldehyde-3-Phosphate DehydrogenasesHealthHemeHemeproteinsHost DefenseHumanIndividualInflammationLiquid substanceLungMeasuresMediatingMetalloproteinsModelingMusMuscle CellsMuscle functionMuscle relaxantsNOS1 geneNOS2A geneNOS3 geneNitratesNitric OxideNitric Oxide SynthaseNitritesOxidation-ReductionOxidoreductasePathway interactionsPatient CarePatientsPharmaceutical PreparationsPharmacologyPlayProductionProsthesisPulmonary HypertensionRecyclingRefractoryResearchRespiratory physiologyRestRoleSKIL geneSliceSmooth MuscleSoluble Guanylate CyclaseSulfhydryl CompoundsSystemTXN geneTestingTranslatingUp-RegulationVascular Smooth Muscleairway epitheliumairway hyperresponsivenessairway inflammationasthmaticasthmatic airwaybaseclinically relevantcytokinedesensitizationexperimental studyheme aimprovedin vivomacrophagemembermouse modelnovelnovel therapeutic interventionpreventprogramsreceptorrespiratory smooth muscleresponserestoration
项目摘要
ABSTRACT - PROJECT 3
Metalloproteins that contain a heme prosthetic group (hemeproteins) are essential to lung functions, including
airway host defense and inflammation [inducible nitric oxide (NO) synthase (iNOS)], and bronchomotor tone
[soluble guanylate cyclase (sGC)]. We recently discovered that NO inhibits heme insertion into apo-proteins by
the S-nitrosyation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which functions in heme transport
and insertion. Recycling GAPDH is dependent on cellular redox and S-denitrosylase enzymes, i.e. GSNO
reductase (GSNOR) or thioredoxin 1 (Trx1). These exciting findings and longstanding interactions with
Program members in the study of asthma over the years made it a natural step to investigate whether the high-
levels of NO in the asthmatic airway blocks hemeprotein maturation. Our preliminary results show that
asthmatic airway epithelium escapes NO-mediated inhibition of heme insertion by upregulation of denitrosylase
pathways, enabling the expression of active iNOS, but that airway smooth muscle cells are overwhelmed by
NO at the levels produced in the asthmatic airway, with consequent loss of heme-replete sGC. New
preliminary data generated in murine models of asthma and in the human precision cut lung slice model
suggest that heme-independent sGC-activators are strikingly effective bronchodilators. Thus, we will test the
hypothesis that thiol denitrosylase systems enable continuous airway epithelial NO production by iNOS in
asthma by restoration of hemeprotein maturation, but that the NO overwhelms smooth muscle denitrosylase
systems, compromising maturation & function of the sGC in smooth muscle, which results in
bronchoconstriction and airway hyper-reactivity. We plan concurrent mechanistic studies and studies of the
bronchodilator response to novel pharmacologic sGC agonists in (i) primary airway smooth muscle cells from
healthy and asthmatic airways, (ii) precision cut human lung slice model and (iii) mouse models of asthma
using genetically modified mice (including NOS1,2,&3 -/-, GSNOR-/- and smooth muscle specific sGC-/-). Also,
we will study hemeprotein maturation in airway epithelial cells freshly obtained from healthy individuals and
asthmatics with low or high FENO to help verify clinical relevance and potentially endotype sGC-agonist
responders. sGC agonists will be tested in order to translate the discoveries to patient care soon. This
research will provide the first information on hemeprotein maturation in healthy and asthmatic airway, and test
connections between dysregulation of hemeprotein maturation and the bronchoconstriction and inflammation
characteristic of asthma.
摘要-项目3
含有血红素辅基的金属蛋白(血红素蛋白)对肺功能至关重要,包括
气道宿主防御和炎症[诱导型一氧化氮(NO)合酶(iNOS)]和支气管张力
[可溶性鸟苷酸环化酶(sGC)]。我们最近发现NO通过抑制血红素插入脱辅基蛋白,
在血红素转运中起作用的甘油醛-3-磷酸脱氢酶(GAPDH)的S-亚硝基化
和插入。GAPDH的再循环依赖于细胞氧化还原和S-脱硝酶,即GSNO
还原酶(GSNOR)或硫氧还蛋白1(Trx 1)。这些令人兴奋的发现和长期的互动,
多年来研究哮喘的项目成员很自然地调查了高血压是否是一种疾病,
哮喘气道中的NO水平阻断血红素蛋白成熟。我们的初步结果显示,
哮喘气道上皮细胞通过上调脱硝酶逃避NO介导的血红素插入抑制
通路,使活性iNOS的表达,但气道平滑肌细胞被淹没
哮喘气道中产生的NO水平,随之而来的是充满血红素的sGC的损失。新
在哮喘小鼠模型和人类精确切割肺切片模型中产生的初步数据
表明血红素非依赖性sGC激活剂是显著有效的支气管扩张剂。我们将测试
假设硫醇脱硝酶系统能够通过诱导型一氧化氮合酶持续产生气道上皮NO,
哮喘通过血红素蛋白成熟的恢复,但NO抑制平滑肌脱硝酶
系统,损害sGC在平滑肌中的成熟和功能,这导致
支气管收缩和气道高反应性。我们计划同时进行机理研究和
(i)来自以下的原发性气道平滑肌细胞中对新型药理学sGC激动剂的支气管扩张剂反应:
健康和哮喘气道,(ii)精确切割人肺切片模型和(iii)哮喘小鼠模型
使用遗传修饰的小鼠(包括NOS 1,2,&3-/-、GSNOR-/-和平滑肌特异性sGC-/-)。还有,
我们将研究从健康个体新鲜获得的气道上皮细胞中血红素蛋白的成熟,
低或高FENO的哮喘患者,以帮助验证临床相关性和潜在的内源性sGC激动剂
响应者。将对sGC激动剂进行测试,以便将这些发现很快转化为患者护理。这
这项研究将提供健康和哮喘气道中血红素蛋白成熟的第一个信息,
血红素蛋白成熟失调与支气管收缩和炎症的关系
哮喘的特征。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DENNIS J STUEHR其他文献
DENNIS J STUEHR的其他文献
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{{ truncateString('DENNIS J STUEHR', 18)}}的其他基金
Defining a pathway for mitochondrial heme trafficking
定义线粒体血红素运输途径
- 批准号:
10733705 - 财政年份:2023
- 资助金额:
$ 31.39万 - 项目类别:
Coordinate control of hemeprotein maturation and function by cell chaperones, heme, and nitric oxide
细胞伴侣、血红素和一氧化氮协调控制血红素蛋白的成熟和功能
- 批准号:
10207671 - 财政年份:2019
- 资助金额:
$ 31.39万 - 项目类别:
Coordinate control of hemeprotein maturation and function by cell chaperones, heme, and nitric oxide
细胞伴侣、血红素和一氧化氮协调控制血红素蛋白的成熟和功能
- 批准号:
10428556 - 财政年份:2019
- 资助金额:
$ 31.39万 - 项目类别:
New mechanism and regulation of intracellular heme delivery in mammals
哺乳动物细胞内血红素输送的新机制和调控
- 批准号:
8241962 - 财政年份:2011
- 资助金额:
$ 31.39万 - 项目类别:
New mechanism and regulation of intracellular heme delivery in mammals
哺乳动物细胞内血红素输送的新机制和调控
- 批准号:
8636030 - 财政年份:2011
- 资助金额:
$ 31.39万 - 项目类别:
New mechanism and regulation of intracellular heme delivery in mammals
哺乳动物细胞内血红素输送的新机制和调控
- 批准号:
8449268 - 财政年份:2011
- 资助金额:
$ 31.39万 - 项目类别:
New mechanism and regulation of intracellular heme delivery in mammals
哺乳动物细胞内血红素输送的新机制和调控
- 批准号:
8082579 - 财政年份:2011
- 资助金额:
$ 31.39万 - 项目类别:
2009 Nitric Oxide Gordon Research Conference
2009 年一氧化氮戈登研究会议
- 批准号:
7600784 - 财政年份:2009
- 资助金额:
$ 31.39万 - 项目类别:
Nitric Oxide Synthases As Oxidative And Therapeutic Agents
作为氧化剂和治疗剂的一氧化氮合成酶
- 批准号:
7664775 - 财政年份:2008
- 资助金额:
$ 31.39万 - 项目类别:
Redor Pathways Regulating Nemeprotein Maturation in Asthma
Redor 通路调节哮喘中的 Neme 蛋白成熟
- 批准号:
9015473 - 财政年份:2006
- 资助金额:
$ 31.39万 - 项目类别: