Targeting mechanisms contributing to vascular dysfunction and pain in sickle cell disease
导致镰状细胞病血管功能障碍和疼痛的靶向机制
基本信息
- 批准号:10424765
- 负责人:
- 金额:$ 8.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-04-04 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:Absence of pain sensationAcuteAcute PainAttenuatedBiological AvailabilityBiologyBloodBlood CirculationBlood VesselsChronicClinical TrialsCytoplasmic GranulesDNADataDefectEndotheliumErythrocytesFDA approvedFrightGeneticGoalsHemeHeme IronHemoglobinHemolysisHereditary DiseaseHistonesHospitalizationHumanHyperalgesiaIn VitroIndividualInflammationInflammatoryInjuryLaboratoriesLeadLifeMediatingMicrovascular DysfunctionMusNerveNervous system structureNeurogenic InflammationNeuronsNuclearOpioidOxidative StressPainPatientsPeptide HydrolasesPharmaceutical PreparationsPharmacologyPlayPoint MutationPorphyrinsProcessQuality of lifeRecurrenceRoleSickle CellSickle Cell AnemiaSickle Cell TraitSickle HemoglobinSourceStimulusSystemTLR4 geneTNF geneTestingTissuesTransgenic OrganismsTranslationsTryptaseVascular DiseasesVascular Permeabilitiesaddictionaxon injurybasechronic paincongeniccytokinecytotoxicendoplasmic reticulum stressextracellularfunctional outcomesgranulocytehemoglobin AAimprovedin vivoinfancyinhibitor/antagonistmast cellmouse modelmultidisciplinaryneuroinflammationneurotransmissionneurovascularnovelopioid useparoxysmal nocturnal hemoglobinuriapathogenpreventrelating to nervous systemresponsesicklingside effecttranslational approachvascular injuryvaso-occlusive crisisvaso-occlusive pain
项目摘要
Summary/Abstract
Sickle cell disease (SCD), a recessive inherited disorder caused by a point mutation in the hemoglobin chain of
red blood cells (RBCs). Microvascular dysfunction is central to the pathobiology of SCD, leading to life-
threatening consequences. A major consequence is occlusion of activated microvasculature with sickle RBCs
leading to unpredictable and frequent episodes of acute pain called vaso-occlusive crises (VOC), frequent
hospitalization and poor quality of life. Many individuals with SCD suffer chronic pain that may start during
infancy and continue to increase throughout life. Opioids are the mainstay for treatment but their side-effects
and fear of addiction remain a major concern. Hence, a major unmet need is to prevent and/or treat pain more
effectively. VOC is associated with increased hemolysis that releases free heme. Our preliminary data reveal
that administration of free heme causes hyperalgesia (pain) in transgenic sickle mice expressing human sickle
hemoglobin (Hb) and in control mice expressing normal human HbA. Our preliminary data shows that heme
stimulates mast-cell extracellular traps (ETs) by releasing nuclear DNA and citrullinated histones. Mast-
cell activation promotes hyperalgesia in sickle mice. We hypothesize that heme-induced mast-cell
activation leads to release of citrullinated histones and noxious substances and contributes to
inflammation, vascular dysfunction and axonal injury leading to vasoocclusion and hyperalgesia in
SCD (Schema I). Mast cells may play a causal role in VOC and chronic pain in SCD. Targeting mast cells
will ameliorate VOC and pain at its source. We will test our hypothesis using a translational approach with
four specific aims to establish whether, heme contributes to chronic and/or acute hyperalgesia (Aim1),
heme contributes to chronic/acute pain via mast-cell activation (Aim2), and heme-induced hyperalgesia
is driven by novel mast cell–dependent mechanisms leading to axonal and vascular injury (Aim3),
including, release of inflammatory cytokines, proteases, ETs with DNA and citrullinated histones from mast
cells that cause axonal injury in the periphery and DRG neurons, and endothelial activation via endoplasmic
reticulum stress. Aim4 will entail determining whether targeting the mechanisms of heme-induced mast-
cell activation attenuates hyperalgesia and vaso-occlusion. We will use genetic and pharmacological
approaches, namely [i] humanized transgenic HbSS-BERK sickle mice exclusively expressing human sickle
Hb, [ii] HbAA-BERK control mice expressing normal human HbA, [iii] sickle mice deleted for, [a] mast cells or
[b] TLR4 and their congenic controls; and mechanism-specific pharmacological inhibitors to prevent vaso-
occlusion and pain. Mouse models and biologicals are available in our laboratories. By using multiple
strategies in vivo and in vitro, involving mast cell–mediated hyperalgesia and their targeting with novel
and/or FDA-approved drugs, we expect that our observations will lead to translationally relevant
functional outcomes—reduction of VOC and acute as well as chronic pain in SCD.
摘要/文摘
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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Kalpna Gupta其他文献
Kalpna Gupta的其他文献
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{{ truncateString('Kalpna Gupta', 18)}}的其他基金
Summer Mentoring and Research Training (SMART)
暑期指导和研究培训(SMART)
- 批准号:
10207087 - 财政年份:2021
- 资助金额:
$ 8.75万 - 项目类别:
Summer Mentoring and Research Training (SMART)
暑期指导和研究培训(SMART)
- 批准号:
10377411 - 财政年份:2021
- 资助金额:
$ 8.75万 - 项目类别:
Summer Mentoring and Research Training (SMART)
暑期指导和研究培训(SMART)
- 批准号:
10614485 - 财政年份:2021
- 资助金额:
$ 8.75万 - 项目类别:
Targeting mechanisms contributing to vascular dysfunction and pain in sickle cell disease
导致镰状细胞病血管功能障碍和疼痛的靶向机制
- 批准号:
10076288 - 财政年份:2020
- 资助金额:
$ 8.75万 - 项目类别:
Targeting mechanisms contributing to vascular dysfunction and pain in sickle cell disease
导致镰状细胞病血管功能障碍和疼痛的靶向机制
- 批准号:
9906937 - 财政年份:2019
- 资助金额:
$ 8.75万 - 项目类别:
Targeting mechanisms contributing to vascular dysfunction and pain in sickle cell disease
导致镰状细胞病血管功能障碍和疼痛的靶向机制
- 批准号:
10434654 - 财政年份:2019
- 资助金额:
$ 8.75万 - 项目类别:
Targeting mechanisms contributing to vascular dysfunction and pain in sickle cell disease
导致镰状细胞病血管功能障碍和疼痛的靶向机制
- 批准号:
10095111 - 财政年份:2019
- 资助金额:
$ 8.75万 - 项目类别:
Cannabinoid-based therapy and approaches to quantify pain in sickle cell disease
基于大麻素的疗法和量化镰状细胞病疼痛的方法
- 批准号:
8467856 - 财政年份:2013
- 资助金额:
$ 8.75万 - 项目类别:
Cannabinoid-based therapy and approaches to quantify pain in sickle cell disease
基于大麻素的疗法和量化镰状细胞病疼痛的方法
- 批准号:
8722605 - 财政年份:2013
- 资助金额:
$ 8.75万 - 项目类别:
Cannabinoid-based therapy and approaches to quantify pain in sickle cell disease
基于大麻素的疗法和量化镰状细胞病疼痛的方法
- 批准号:
8877627 - 财政年份:2013
- 资助金额:
$ 8.75万 - 项目类别:
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