Activation of cAMP-Mediated Sicke Cell Adhesion
cAMP 介导的病细胞粘附的激活
基本信息
- 批准号:7407406
- 负责人:
- 金额:$ 41.84万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-04-01 至 2008-03-31
- 项目状态:已结题
- 来源:
- 关键词:A kinase anchoring proteinAdenylate CyclaseAdhesionsAdhesivenessAdhesivesAdrenergic ReceptorAgeAgonistBlood VesselsCell AdhesionCell LineCellsCharacteristicsConditionCyclic AMPCyclic AMP-Dependent Protein KinasesDiseaseDisruptionEndothelial CellsEpinephrineExhibitsHumanLaboratoriesLamininLeadLeukocytesLinkMapsMediatingMediator of activation proteinPainPathway interactionsPatientsPhysiologicalPlatelet AdhesivenessPositioning AttributeProcessProductionProtein IsoformsProteinsRat ProteinRattusRecurrenceRoleSickle CellSignal PathwaySignal TransductionSiteStagingStressSystemTestingTherapeutic Interventionadhesion receptorbasedesignin vivonovel therapeuticsreceptorsicklingtherapeutic target
项目摘要
Agonist-induced signaling is a primary mechanism regulating adhesiveness of platelets, leukocytes and other cells. However, RBCs are generally considered to be inert to agonist stimulation; thus signaling in sickle (SS) RBCs by agonists to directly activate SS RBC adhesiveness is relatively unexplored. Because abnormal SS RBC adhesion is believed to contribute to the painful vaso-occlusive crises suffered by sickle cell patients, it is crucial to understand mechanisms that modulate this adhesion. We recently made the important finding that SS RBCs are very responsive to agonist stimulation, resulting in a rapid and pronounced increase in adhesion to multiple vascular proteins. Here we propose to expand upon our
findings that agonist-induced cAMP production results in a protein kinase A-dependent activation of SS RBC adhesion to laminin. Thus, epinephrine and several other physiologic agonists rapidly increase SS RBC adhesion in a subset of patients, providing a potential physiologic link between conditions that elevate these agonists, such as stress and pain, with vaso-occlusion. Here we propose to: 1) establish the basis for epinephrine-responsive and non-responsive sickle cell patient RBCs, 2) identify the receptor subtype(s) involved in epinephrine-induced SS RBC adhesion and identify additional naturally occurring agonists and agonist receptors that induce this process, 3) map the AMP-dependent signaling pathway(s) mediating stimulated SS RBC adhesion to laminin, 4) identify additional vascular proteins that support cAMP-stimulated
SS RBC adhesion and the receptors/sites mediating these adhesive interactions, and 5) determine the role of cAMP-stimulated SS RBC adhesion in an in vivo system. These studies are likely to lead to new therapeutic targets for the disruption of AMP-mediated adhesive interactions in sickle cell patients.
激动剂诱导的信号传导是调节血小板、白细胞和其他细胞增殖的主要机制。然而,RBC通常被认为对激动剂刺激是惰性的;因此通过激动剂在镰状(SS)RBC中直接激活SS RBC的信号传导相对未被探索。由于SS RBC粘附异常被认为是镰状细胞病患者痛苦的血管闭塞性危象的原因,因此了解调节这种粘附的机制至关重要。我们最近取得了重要的发现,SS RBC对激动剂刺激非常敏感,导致与多种血管蛋白的粘附迅速而显著地增加。在这里,我们建议扩大我们的
激动剂诱导的cAMP产生导致SS RBC粘附层粘连蛋白的蛋白激酶A依赖性激活。因此,肾上腺素和几种其他生理激动剂在一部分患者中迅速增加SS RBC粘附,从而在升高这些激动剂的条件(如压力和疼痛)与血管闭塞之间提供了潜在的生理联系。在此,我们建议:1)建立肾上腺素反应性和非反应性镰状细胞患者RBC的基础,2)鉴定参与肾上腺素诱导的SS RBC粘附的受体亚型,并鉴定诱导该过程的另外的天然存在的激动剂和激动剂受体,3)绘制介导刺激的SS RBC粘附至层粘连蛋白的AMP依赖性信号传导途径,4)鉴定支持cAMP刺激的SS RBC粘附的另外的血管蛋白,
SS RBC粘附和介导这些粘附相互作用的受体/位点,和5)确定cAMP刺激的SS RBC粘附在体内系统中的作用。这些研究可能会导致新的治疗靶点的破坏AMP介导的粘附相互作用的镰状细胞患者。
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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Leslie V. Parise其他文献
Integrin αa<sub>4</sub>β<sub>1</sub> and Glycoprotein IV (CD36) Are Expressed on Circulating Reticulocytes in Sickle Cell Anemia
- DOI:
10.1182/blood.v82.12.3548.3548 - 发表时间:
1993-12-15 - 期刊:
- 影响因子:
- 作者:
Christopher C. Joneckis;Rhonda L. Ackley;Eugene P. Orringer;Elizabeth A. Wayner;Leslie V. Parise - 通讯作者:
Leslie V. Parise
Phorbol Ester Enhances Integrin αIIbβ3-Dependent Adhesion of Human Erythroleukemic Cells to Activation-Dependent Monoclonal Antibodies
- DOI:
10.1182/blood.v87.3.968.bloodjournal873968 - 发表时间:
1996-02-01 - 期刊:
- 影响因子:
- 作者:
Christel Boudignon-Proudhon;Pankaj M. Patel;Leslie V. Parise - 通讯作者:
Leslie V. Parise
Lack Of Inhibition Of Thromboxane Production Despite Inhibition Of Platelet Function By 1,3-Bis(2 Chloroethyl)-1-Nitrosourea (BCNU)
尽管 1,3-双(2 氯乙基)-1-亚硝基脲 (BCNU) 抑制血小板功能,但对血栓素产生缺乏抑制作用
- DOI:
- 发表时间:
1981 - 期刊:
- 影响因子:6.7
- 作者:
Leslie V. Parise;D. Venton;G. C. Breton - 通讯作者:
G. C. Breton
Leslie V. Parise的其他文献
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{{ truncateString('Leslie V. Parise', 18)}}的其他基金
2009 Cell Biology of Megakaryocytes and Platelets Gordon Research Conference
2009年巨核细胞和血小板细胞生物学戈登研究会议
- 批准号:
7611180 - 财政年份:2009
- 资助金额:
$ 41.84万 - 项目类别:
Target discovery in platelets by in situ proteome reactivity profiling
通过原位蛋白质组反应性分析发现血小板靶标
- 批准号:
7295727 - 财政年份:2006
- 资助金额:
$ 41.84万 - 项目类别:
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