The Role of Vascular Calprotectin in Arteriovenous Fistula Maturation
血管钙卫蛋白在动静脉瘘成熟中的作用
基本信息
- 批准号:10467193
- 负责人:
- 金额:$ 44.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-01 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:AgeAmericanArteriovenous fistulaAutomobile DrivingBasic ScienceBiologyBloodBlood VesselsBlood flowCXCL12 geneCathetersChronic Kidney FailureClinicalDataDevelopmentDialysis patientsDialysis procedureEctopic ExpressionEnd stage renal failureExperimental Animal ModelFailureFibrosisFistulaFunctional disorderGene ExpressionGeneticGenetic TranscriptionGoalsHemodialysisHumanHyperplasiaInflammationInflammatoryInjectionsInterventionKidney DiseasesKnockout MiceLeadLeukocyte L1 Antigen ComplexLifeMediatingMedical Care CostsMolecularMorbidity - disease rateMusOutcomeOutcome StudyPathogenicityPathologicPatientsPhenotypePostoperative PeriodPublishingQuality of lifeResearchRetrospective cohortRiskRoleSamplingSecureSignal TransductionSmooth Muscle MyocytesStenosisStudy modelsTamoxifenTechniquesTestingTranslational ResearchUp-RegulationValidationVenousbiobankcell typecohortdesignexperienceimprovedinhibitormedical complicationmortalitynew therapeutic targetnovel therapeuticspreventresponsesexsystemic inflammatory responsetargeted treatmenttranscription factor
项目摘要
Over 600,000 Americans live with end-stage renal disease (ESRD), and ∼468,000 of them are dialysis patients who depend on a functional vascular access to extend their lives. A mature arteriovenous (A-V) fistula is the preferred dialysis access due to its higher patency rates and lower medical costs compared to synthetic grafts and central venous catheters. However, ~40% of newly created fistulas fail to mature, i.e., they are not usable for dialysis because stenosis prevents them from reaching the necessary blood flow. There is paucity of research into the mechanisms underlying postoperative stenosis in A-V fistulas, despite its negative impact on morbidity, mortality, and quality of life of these patients. This translational proposal establishes the mechanistic relationship among the CXCL12 and PU.1/calprotectin signaling network, inward remodeling, and fistula outcomes in order to design targeted therapies to prevent maturation failure. Our proposal is built on strong scientific premises that suggest a mechanistic relationship between postoperative accumulation of calprotectin in A-V fistulas caused by ectopic expression of the transcription factor PU.1 and inward remodeling that causes fistula failure. Our overarching hypothesis is that smooth muscle cell (SMC)-derived calprotectin increases the risk for stenosis and failure in newly created A-V fistulas. Our mechanistic hypothesis is that elevated CXCL12 level in hemodialysis patients leads to ectopic expression of PU.1 in the vasculature and the subsequent accumulation of calprotectin in SMCs. The released calprotectin exacerbates inflammation, fibrosis, and intimal hyperplasia (IH) after fistula creation. We will test our hypothesis in three specific aims and five experimental layouts that will prove: 1) the contribution of calprotectin to fistula inward remodeling; 2) the underlying mechanisms by which CXCL12 and PU.1 increases calprotectin and the risk of A-V fistula failure; and 3) the relationship between PU.1 and fistula maturation outcomes in a human cohort. We will combine fine microsurgical techniques and knockout mice to successfully achieve our goals. We will also interrogate a human biorepository of 100 randomly selected patients undergoing creation of two-stage brachiobasilic transposition fistulas to search for associations between the levels of PU.1 after venous remodeling and inadequate maturation. In conclusion, with the successful accomplishment of this proposal, we are paving the way for the design of new drugs and cell type-specific interventions to effectively target A-V fistula fibrosis and IH and reduce vascular access complications.
超过60万美国人患有终末期肾病(ESRD),其中约468,000人是依靠功能性血管通道延长生命的透析患者。成熟的动静脉(A- v)瘘是首选的透析途径,因为与合成移植物和中心静脉导管相比,它的通畅率更高,医疗费用更低。然而,约40%的新造瘘管不能成熟,也就是说,它们不能用于透析,因为狭窄阻止它们到达必要的血液流动。尽管A-V瘘对患者的发病率、死亡率和生活质量有负面影响,但对其术后狭窄机制的研究仍很缺乏。该翻译建议建立CXCL12和PU.1/calprotectin信号网络、内向重塑和瘘管结局之间的机制关系,以便设计靶向治疗来预防成熟失败。我们的建议是建立在强有力的科学前提之上的,这表明由转录因子PU.1的异位表达引起的a - v瘘术后钙保护蛋白的积累与导致瘘失败的内向重塑之间存在机制关系。我们的主要假设是平滑肌细胞(SMC)来源的钙保护蛋白增加了新造的A-V瘘狭窄和失败的风险。我们的机制假设是血液透析患者中CXCL12水平升高导致PU.1在脉管系统中的异位表达以及随后在SMCs中钙保护蛋白的积累。释放的钙保护蛋白加重了瘘形成后的炎症、纤维化和内膜增生(IH)。我们将通过三个具体目标和五个实验布局来验证我们的假设:1)钙保护蛋白对瘘管内重构的贡献;2) CXCL12和PU.1增加钙保护蛋白和A-V瘘失败风险的潜在机制;3)人类队列中PU.1与瘘管成熟结果的关系。我们将结合精细的显微外科技术和基因敲除小鼠来成功实现我们的目标。我们还将询问100名随机选择的两期肱基础移位瘘管患者的人类生物库,以寻找静脉重塑后PU.1水平与成熟不足之间的关系。总之,随着这一建议的成功完成,我们正在为设计新的药物和细胞类型特异性干预措施铺平道路,以有效地靶向A-V瘘纤维化和IH,并减少血管通路并发症。
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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Roberto Irenardo Vazquez Padron其他文献
Roberto Irenardo Vazquez Padron的其他文献
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{{ truncateString('Roberto Irenardo Vazquez Padron', 18)}}的其他基金
The Role of Vascular Calprotectin in Arteriovenous Fistula Maturation
血管钙卫蛋白在动静脉瘘成熟中的作用
- 批准号:
10609080 - 财政年份:2022
- 资助金额:
$ 44.83万 - 项目类别:
The Multiple Roles of Lysyl Oxidase in Arteriovenous Fistula Failure
赖氨酰氧化酶在动静脉内瘘衰竭中的多重作用
- 批准号:
10454770 - 财政年份:2020
- 资助金额:
$ 44.83万 - 项目类别:
The Multiple Roles of Lysyl Oxidase in Arteriovenous Fistula Failure
赖氨酰氧化酶在动静脉内瘘衰竭中的多重作用
- 批准号:
10618919 - 财政年份:2020
- 资助金额:
$ 44.83万 - 项目类别:
The Multiple Roles of Lysyl Oxidase in Arteriovenous Fistula Failure
赖氨酰氧化酶在动静脉内瘘衰竭中的多重作用
- 批准号:
9891408 - 财政年份:2020
- 资助金额:
$ 44.83万 - 项目类别:
Genetics of In-Stent Restenosis: The Mouse to Human Strategy
支架内再狭窄的遗传学:从小鼠到人类的策略
- 批准号:
7680554 - 财政年份:2009
- 资助金额:
$ 44.83万 - 项目类别:
Genetics of In-Stent Restenosis: The Human Strategy
支架内再狭窄的遗传学:人类策略
- 批准号:
8265729 - 财政年份:2009
- 资助金额:
$ 44.83万 - 项目类别:
Genetics of In-Stent Restenosis: The Mouse to Human Strategy
支架内再狭窄的遗传学:从小鼠到人类的策略
- 批准号:
7923378 - 财政年份:2009
- 资助金额:
$ 44.83万 - 项目类别:
Genetics of In-Stent Restenosis: The Mouse to Human Strategy
支架内再狭窄的遗传学:从小鼠到人类的策略
- 批准号:
8073065 - 财政年份:2009
- 资助金额:
$ 44.83万 - 项目类别:
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