Dual Role of Lysyl Oxidase in Arteriovenous Fistula Failure
赖氨酰氧化酶在动静脉内瘘衰竭中的双重作用
基本信息
- 批准号:10019524
- 负责人:
- 金额:$ 38.29万
- 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:2019-09-17 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAnimalsAreaArteriesArteriovenous fistulaAttenuatedBiologicalBiomechanicsBlood VesselsBlood flowCathetersCell NucleusCellsChIP-seqCollagenComplexComplicationCopperDataDockingElastinEnd stage renal failureEnzymesEpigenetic ProcessExperimental Animal ModelExperimental ModelsExtracellular ProteinExtracellular SpaceFailureFamily suidaeFibrosisFistulaFunctional disorderGene ExpressionGenesGenetic TranscriptionGoalsHemodialysisHistone CodeHistone H3HistonesHumanHyperplasiaIn SituIn VitroInterventionKnockout MiceLimb structureLocationLysineMaintenanceManuscriptsMass Spectrum AnalysisMedialMediatingMedicalMicroscopyModelingMorbidity - disease rateMusMyographyNuclearNucleosomesOperative Surgical ProceduresOutcome StudyPathogenicityPatientsPharmacologyPhenotypePostoperative PeriodPre-Clinical ModelProceduresProtein-Lysine 6-OxidasePublishingQuality of lifeResearchRiskRoleSafetySecureSiteSmooth Muscle MyocytesSourceStenosisTechniquesTestingThickThrombosisTimeUp-RegulationVeinsVenousamine oxidasearmbiobankcell typecohortconditional knockoutcostcrosslinkdesignhistone modificationimprovedinhibitor/antagonistmedical complicationmortalitymyocardinnanofiberneointima formationnew therapeutic targetnovelnovel therapeutic interventionnovel therapeuticspre-clinicalpreservationpreventpromoterprotein crosslinkscaffoldtranscriptome sequencingtranscriptomics
项目摘要
The failure of hemodialysis arteriovenous (A-V) fistulas, which are surgically created by
anastomosing a vein to a nearby artery, remains an unmet medical problem in the field of vascular
surgery. In fact, approximately four out of 10 newly created fistulas will require a surgical or
intravascular salvage procedure to reach maturation and become suitable for hemodialysis.
Arteriovenous fistulas fail because stenosis (vascular narrowing) prevents high blood
flows through the venous limb and increases the risk for thrombosis. We recently
discovered that stenosis occurs due to excessive medial fibrosis and increased
extracellular protein crosslinking, and is aggravated by intimal hyperplasia (IH) in a human
cohort of 165 patients. Therefore, our overall goals are, first, to establish the
cause-and-effect relationship between LOX, the most important enzyme responsible for
crosslinking, and A-V fistula failure and, second, to design new therapeutics to facilitate A-V
fistula maturation through perivascular delivery of LOX inhibitors. Our proposal is built on strong
scientific premises (manuscripts and unique preliminary data) that suggest a mechanistic
relationship between postoperative upregulation of LOX in native fistulas and the improper
wall remodeling that causes fistula failure. Specifically, our overarching hypothesis is
that LOX activity is a major contributor in A-V fistula maturation failure. Our primary hypothesis
is that postsurgical upregulation of nuclear LOX deaminates lysine residues in histones to disrupt
the epigenetic landscape that secures contractile gene expression in SMCs, thereby facilitating
their maladaptive phenotypic switch, neointima formation, and fibrosis of newly created A-V
fistulas. Our secondary hypothesis is that inhibition of LOX prevents inward remodeling
in a preclinical A-V fistula model in swine. We will test our hypothesis in three
specific aims that will: 1) identify the cellular source of LOX after A-V fistula creation, 2)
demonstrate the impact of LOX mediated histone modifications on the SMC phenotype after fistula
creation, and
3) demonstrate that LOX inhibitors attenuate inward remodeling, IH, and stenosis in preclinical A-V
fistulas in swine. We will use fine microsurgical techniques in novel conditional
knockout mice and in vitro and in situ models to successfully achieve our goals. We
will also use a preclinical model in swine to demonstrate the efficacy and safety of
perivascular delivery of LOX inhibitors in preventing A-V fistula failure. 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 reduce vascular
access complications.
血液透析动静脉(A-V)瘘的失败,这是通过手术创建的
将静脉与附近的动脉吻合,仍然是血管领域尚未解决的医学问题
外科手术。事实上,大约十分之四的新形成的瘘管需要手术或
血管内挽救程序以达到成熟并适合血液透析。
动静脉瘘失败是因为狭窄(血管变窄)可防止高血
流经肢体静脉并增加血栓形成的风险。我们最近
发现狭窄是由于过度的内侧纤维化和增加而发生的
细胞外蛋白质交联,并因人类内膜增生 (IH) 而加剧
队列由 165 名患者组成。因此,我们的总体目标是,首先,建立
LOX(最重要的酶)之间的因果关系
交联和 A-V 瘘管失败,其次,设计新的疗法以促进 A-V
通过血管周围递送 LOX 抑制剂促进瘘管成熟。我们的建议建立在强有力的基础上
表明机械论的科学前提(手稿和独特的初步数据)
自体瘘管术后LOX上调与不当治疗之间的关系
导致瘘管失败的管壁重塑。具体来说,我们的总体假设是
LOX 活性是 A-V 瘘成熟失败的主要原因。我们的主要假设
是核 LOX 的术后上调使组蛋白中的赖氨酸残基脱氨以破坏
确保 SMC 中收缩基因表达的表观遗传景观,从而促进
它们的适应不良表型转换、新内膜形成和新产生的 A-V 纤维化
瘘管。我们的次要假设是,抑制 LOX 可以防止向内重塑
在猪的临床前 A-V 瘘模型中。我们将分三步检验我们的假设
具体目标将:1) 确定 A-V 瘘创建后 LOX 的细胞来源,2)
证明 LOX 介导的组蛋白修饰对瘘管后 SMC 表型的影响
创造,以及
3) 证明 LOX 抑制剂可减弱临床前 A-V 中的内向重塑、IH 和狭窄
猪的瘘管。我们将在新颖的条件下使用精细的显微外科技术
敲除小鼠以及体外和原位模型成功实现了我们的目标。我们
还将使用猪的临床前模型来证明其有效性和安全性
LOX 抑制剂的血管周围递送预防 A-V 瘘失败。总之,随着
这项提案的成功完成,我们正在为新药的设计和
细胞类型特异性干预措施可有效针对 A-V 瘘纤维化并减少血管
访问并发症。
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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YAN-TING E. SHIU其他文献
YAN-TING E. SHIU的其他文献
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{{ truncateString('YAN-TING E. SHIU', 18)}}的其他基金
Dual Role of Lysyl Oxidase in Arteriovenous Fistula Failure
赖氨酰氧化酶在动静脉内瘘衰竭中的双重作用
- 批准号:
9913910 - 财政年份:2019
- 资助金额:
$ 38.29万 - 项目类别:
Dual Role of Lysyl Oxidase in Arteriovenous Fistula Failure
赖氨酰氧化酶在动静脉内瘘衰竭中的双重作用
- 批准号:
10214287 - 财政年份:2019
- 资助金额:
$ 38.29万 - 项目类别:
Dual Role of Lysyl Oxidase in Arteriovenous Fistula Failure
赖氨酰氧化酶在动静脉内瘘衰竭中的双重作用
- 批准号:
10432141 - 财政年份:2019
- 资助金额:
$ 38.29万 - 项目类别:
Dual Role of Lysyl Oxidase in Arteriovenous Fistula Failure
赖氨酰氧化酶在动静脉内瘘衰竭中的双重作用
- 批准号:
10507700 - 财政年份:2019
- 资助金额:
$ 38.29万 - 项目类别:
Dual Role of Lysyl Oxidase in Arteriovenous Fistula Failure
赖氨酰氧化酶在动静脉内瘘衰竭中的双重作用
- 批准号:
10432703 - 财政年份:2019
- 资助金额:
$ 38.29万 - 项目类别:
Dual Role of Lysyl Oxidase in Arteriovenous Fistula Failure
赖氨酰氧化酶在动静脉内瘘衰竭中的双重作用
- 批准号:
10190926 - 财政年份:2019
- 资助金额:
$ 38.29万 - 项目类别:
Dual Role of Lysyl Oxidase in Arteriovenous Fistula Failure
赖氨酰氧化酶在动静脉内瘘衰竭中的双重作用
- 批准号:
10605271 - 财政年份:2019
- 资助金额:
$ 38.29万 - 项目类别:
Mechanisms of imbalanced inward and outward arteriovenous fistula remodeling
内外不平衡动静脉内瘘重塑机制
- 批准号:
10614369 - 财政年份:2018
- 资助金额:
$ 38.29万 - 项目类别:
Mechanisms of imbalanced inward and outward arteriovenous fistula remodeling
内外不平衡动静脉内瘘重塑机制
- 批准号:
10047699 - 财政年份:2018
- 资助金额:
$ 38.29万 - 项目类别:
Mechanisms of imbalanced inward and outward arteriovenous fistula remodeling
内外不平衡动静脉内瘘重塑机制
- 批准号:
10292935 - 财政年份:2018
- 资助金额:
$ 38.29万 - 项目类别:
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