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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：
10214287
负责人：
YAN-TING E. SHIU
金额：
$ 7.98万
依托单位：
UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
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：
https://reporter.nih.gov/project-details/10214287
关键词：
Animal Model Animals Area Arteries Arteriovenous fistula Attenuated Biological Biomechanics Blood Vessels Blood flow Catheters Cell Nucleus Cells ChIP-seq Collagen Complex Complication Copper Data Docking Elastin End stage renal failure Enzymes Epigenetic Process Experimental Animal Model Experimental Models Extracellular Protein Extracellular Space Failure Family suidae Fibrosis Fistula Functional disorder Gene Expression Genes Genetic Transcription Goals Hemodialysis Histone Code Histone H3 Histones Human Hyperplasia In Situ In Vitro Intervention Knockout Mice Limb structure Location Lysine Maintenance Manuscripts Mass Spectrum Analysis Medial Mediating Medical Microscopy Modeling Morbidity - disease rate Mus Myography Nuclear Nucleosomes Operative Surgical Procedures Outcome Study Pathogenicity Patients Pharmacology Phenotype Postoperative Period Pre-Clinical Model Procedures Protein-Lysine 6-Oxidase Publishing Quality of life Research Risk Role Safety Secure Site Smooth Muscle Myocytes Source Stenosis Techniques Testing Thick Thrombosis Time Up-Regulation Veins Venous amine oxidase arm biobank cell type cohort conditional knockout cost crosslink design histone modification improved inhibitor/antagonist medical complication mortality myocardin nanofiber neointima formation new therapeutic target novel novel therapeutic intervention novel therapeutics pre-clinical preservation prevent promoter protein crosslink scaffold transcriptome sequencing transcriptomics

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)瘘的失败在血管领域，静脉与附近动脉的吻合仍然是一个尚未解决的医学问题。做手术。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达到成熟，适合血液透析。动静脉瘘失败是因为狭窄(血管狭窄)阻止了高血流经静脉肢体，增加血栓形成的风险。我们最近发现狭窄的发生是由于过度的中层纤维化和增加细胞外蛋白交联，并因人的内膜增生(IH)而加重 165名患者组成的队列。因此，我们的总体目标是，第一，建立最重要的酶--脂氧合酶之间的因果关系其二，设计新的治疗方法以促进动静脉瘘。通过血管周围注射LOX抑制剂使瘘管成熟。我们的建议建立在强有力的基础上科学前提(手稿和独一无二的初步数据) 自然瘘术后LOX上调与手术不当的关系导致瘘管衰竭的室壁重塑。具体地说，我们的首要假设是 LOX活性是动静脉瘘成熟失败的主要原因。我们的主要假设手术后核LOX的上调会使组蛋白中的赖氨酸残基去氨基，从而破坏确保SMC收缩基因表达的表观遗传格局，从而促进他们的不适应表型转换、新生内膜形成和新生的房室纤维化瘘管。我们的第二个假设是抑制LOX可以防止内向重塑在猪的临床前动静脉瘘模型中。我们将在三年内检验我们的假设具体目标将：1)在动静脉瘘形成后确定LOX的细胞来源，2) 脂氧合酶介导组蛋白修饰对瘘管后SMC表型的影响创作，以及 3)证明LOX抑制剂可减轻临床前房室传导阻滞的内向重构、间歇性高血压和狭窄猪的瘘管。我们将在新的条件下使用精细的显微外科技术基因敲除小鼠和体外和原位模型成功实现了我们的目标。我们还将在猪身上使用临床前模型来证明这种药物的有效性和安全性血管周围注射LOX抑制剂预防动静脉瘘失败。总之，有了这一提议的成功完成，我们正在为设计新药和针对细胞类型的干预有效靶向动静脉瘘纤维化和减少血管进入并发症。