Project 3- Role of Leukocyte-Platelet Interactions in Inflammation and Thrombosis
项目 3-白细胞-血小板相互作用在炎症和血栓形成中的作用
基本信息
- 批准号:10268699
- 负责人:
- 金额:$ 53.61万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2026-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdaptive Immune SystemAdhesivesAffectAfrican AmericanArterial InjuryArthritisAttenuatedAutoantibodiesAutoimmune DiseasesBindingBinding SitesBiochemicalBiological MarkersBloodBlood PlateletsBlood VesselsBrainCardiovascular DiseasesCaucasiansCell AdhesionCell Adhesion MoleculesCellsClinicalCognitiveComplexCross-Sectional StudiesCytoplasmic TailCytotoxic agentDepositionDevelopmentDiseaseDisease modelExanthemaFOXP1 geneFatigueFlareFunctional disorderGenerationsGlomerulonephritisHairHemostatic functionHispanicsIRAK1 geneITGAM geneITGB2 geneImmune System DiseasesImmunosuppressive AgentsImpairmentInflammasomeInflammationInflammatoryInnate Immune SystemIntegrinsInterruptionJointsKidneyLaboratoriesLasersLeukocytesLigand BindingLigationLungLupusMacrophage-1 AntigenMediatingMethodsMicrocirculationModelingMolecularMonoclonal AntibodiesMultiple SclerosisMusMutant Strains MiceNatureNuclearObservational StudyOrganPainPathogenesisPatient AgentsPatientsPeptidesPopulationPrevalencePreventionProcessReportingRoleSerumSignal TransductionSiteSkinStable DiseaseStrokeStructureSurvival RateSymptomsSystemic Lupus ErythematosusSystemic diseaseTalinTherapeutic immunosuppressionThrombosisTimeTissuesVasculitisVenousVenous ThrombosisWomanbasechronic painexperienceexperimental studyextracellularforkhead proteinhealth disparityin vivoinsightmacrophagemonocytemouse modelneutrophilnovelnovel therapeuticsreceptorrecruitresponserestenosistherapeutically effectivethromboticvascular injury
项目摘要
PROJECT SUMMARY/ABSTRACT
This translational project will focus on systemic lupus erythematosus (SLE) as a unique disease model
of inflammation and thrombosis. SLE is a complex autoimmune disease. The prevalence of SLE ranges
from 20 to 150 cases per 100,000 population. SLE affects primarily women and there is a significant impact
of health disparities in patients with Lupus. SLE is 2-3 times more prevalent among African American and
Hispanic than among Caucasian women. Patients with SLE can experience significant symptoms, such as
chronic pain, extreme fatigue, hair loss, cognitive issues, and physical impairments that affect every facet
of their lives. Many suffer from cardiovascular disease, strokes, disfiguring rashes, and painful arthritis.
The 10-year survival rate is about 70%. Historically, SLE has been considered as an adaptive immune
system disorder characterized by the presence in patient serum of autoantibodies raised against nuclear
components which deposit in blood vessels, skin, kidney, lung, joints and brain causing tissue damage
and clinical manifestations. New advances in the understanding of SLE pathogenesis have focused on the
innate immune system, with a particular focus on leukocytes (i.e., neutrophils, monocytes) as key players
in perpetuating and amplifying this systemic disease. Currently, there is no prevention or cure for SLE, and
the mainstay of treatment is non-specific immunosuppressive and cytotoxic agents. Thus, there is
significant unmet clinical need in SLE and compelling demand for more effective therapeutic approaches.
Leukocyte-platelet interactions induce bidirectional signals that amplify pro-inflammatory and pro-
thrombotic cellular responses. We have focused on the leukocyte integrin Mac-1 (αMβ2), identifying this
adhesive receptor as a critical molecular determinant of leukocyte recruitment and signaling. Our
laboratory first reported the interaction between Mac-1 and its platelet counter-receptor GPIbα and
determined the molecular basis of GPIb recognition. We established that Mac-1:GPIbα broadly regulates
inflammation in models of vasculitis, glomerulonephritis, and multiple sclerosis as well as arterial
thrombosis. The central hypothesis of this proposal is that the Mac-1:GPIbα interaction is broadly required
for inflammation and initiates pro-inflammatory and prothrombotic signals that promote diverse disease
processes. The specific aims of the project are: 1) To determine the effect of disrupting Mac-1:GPIbα on
the progression and complications of SLE using mouse models; 2) To define the physical determinants of
Mac-1:GPIbα binding and the nature of “outside-in” signals generated by this interaction; and 3) To provide
evidence that clinical SLE disease activity is correlated with biomarkers of the Mac-1:GPIbα interaction.
Because leukocyte-platelet interactions broadly regulate inflammation and thrombosis, understanding the
molecular machinery of this cellular complex will provide important insights for developing new therapies
directed at reducing end-organ damage in SLE and other inflammatory/thrombotic disorders.
项目总结/文摘
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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Daniel I Simon其他文献
406-4 Mice lacking the transcription factor CHF1/Hey2 show decreased arterial neointimal formation after injury and impaired vascular smooth muscle cell responsiveness to growth factors
- DOI:
10.1016/s0735-1097(04)92263-2 - 发表时间:
2004-03-03 - 期刊:
- 影响因子:
- 作者:
Yasuhiko Sakata;Fan Xiang;Zhiping Chen;Yoriko Kiriyama;Caramai N Kamei;Daniel I Simon;Michael T Chin - 通讯作者:
Michael T Chin
Daniel I Simon的其他文献
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{{ truncateString('Daniel I Simon', 18)}}的其他基金
Project 3- Role of Leukocyte-Platelet Interactions in Inflammation and Thrombosis
项目 3-白细胞-血小板相互作用在炎症和血栓形成中的作用
- 批准号:
10661640 - 财政年份:2021
- 资助金额:
$ 53.61万 - 项目类别:
Project 3- Role of Leukocyte-Platelet Interactions in Inflammation and Thrombosis
项目 3-白细胞-血小板相互作用在炎症和血栓形成中的作用
- 批准号:
10471914 - 财政年份:2021
- 资助金额:
$ 53.61万 - 项目类别:
Monocyte Differentiation and Mac-1-Regulated Forkhead
单核细胞分化和 Mac-1 调节的叉头
- 批准号:
6668851 - 财政年份:2003
- 资助金额:
$ 53.61万 - 项目类别:
Monocyte Differentiation and Mac-1-Regulated Forkhead
单核细胞分化和 Mac-1 调节的叉头
- 批准号:
6909940 - 财政年份:2003
- 资助金额:
$ 53.61万 - 项目类别:
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