Novel Molecular Target to Prevent Maturation Failure of Arteriovenous Fistula
预防动静脉瘘成熟失败的新分子靶点
基本信息
- 批准号:10457852
- 负责人:
- 金额:$ 70.5万
- 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:2019-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAnatomyAngiographyAntibodiesApoptosisArterial Occlusive DiseasesArteriovenous fistulaAutologousBiologicalBloodBlood VesselsBlood flowCalcitriolCaliberCarotid ArteriesCathepsin LCellsChronic Kidney FailureCollagenColorDataDefectDevelopmentDoppler UltrasoundElastasesElastinFailureFamily suidaeFemoral veinFibrosisFistulaFunctional disorderGene ExpressionGrowth FactorHMGB1 geneHemodialysisHistologyHumanHyperplasiaIL8 geneImmunologyInfiltrationInflammationInflammation MediatorsInflammatoryInflammatory ResponseInjuryKidney FailureKnowledgeLentivirus VectorLeukocytesLinkMME geneMatrix MetalloproteinasesMeasuresMediatingMediator of activation proteinModelingMolecular BiologyMolecular TargetMorbidity - disease rateMyeloid CellsMyofibroblastNephrologyNitroglycerinOperative Surgical ProceduresOptical Coherence TomographyOutcomePathologyPatientsPeptidesPhase I Clinical TrialsPhenotypePlacebosProteinsResearchSirolimusSiteSmooth Muscle MyocytesStenosisTLR4 geneTNF geneTestingTherapeuticTherapeutic InterventionTumor-infiltrating immune cellsVascular Smooth MuscleVascular remodelingVeinsVenousantagonistbasebevacizumabcell motilitycoronary artery occlusioncytokinedesignexperienceexperimental groupextracellularfemoral arteryhemodynamicsiliac arteryimprovedinhibitormacrophagemigrationmonocytemortalityneutrophilnew therapeutic targetnovelporcine modelpreventreceptorresponsevascular smooth muscle cell proliferation
项目摘要
ABSTRACT
Autologous arteriovenous fistula (AVF) is the preferred vascular access in hemodialysis. However, high rate of
maturation failure due to inadequate blood flow in the outflow vein renders the fistula not useful for hemodialysis.
Neointimal hyperplasia and failure of outward remodeling are the major causes of AVF maturation failure which
is due to inflammation, proliferation, migration, and phenotypic changes of vascular smooth muscle cells
(VSMCs), and extracellular remodeling due to increased matrix metalloproteinases (MMPs). We discovered
increased expression of triggering receptor expressed on myeloid cells-1 (TREM-1), TLR4 and related proteins
in the immature AV fistula. Based on our novel findings, the central hypothesis is that hemodynamic injury
during AVF creation induces inflammation to upregulate TREM-1 and TLR4 to enhance neointimal
hyperplasia and vascular remodeling, and antagonizing TREM-1 and TLR4 will enhance AVF maturation.
This hypothesis will be tested with the following Aims: Aim 1: Our corollary hypothesis predicts that the
administration of TREM-1 and TLR4 antagonists will prevent maturation failure of AVF in swine. We will
examine the effect of a potent inhibitory TREM-1 peptide in the AVF model in pigs. Since TREM-1 could
synergize with TLR4 to mediate the pathology of AVF maturation failure, effect of a potent TLR4 antagonist will
also be examined to prevent maturation failure of AVF. The outcome parameters will include neointimal
hyperplasia in the inflow and outflow segments in the AVF, angiography of the AVF, color Doppler ultrasound,
optical coherence tomography, and histology, immunostaining to analyze inflammation, expression of various
mediators and infiltration of macrophages and neutrophils, VSMC apoptosis, and vascular remodeling. Aim 2:
Our corollary hypothesis predicts that the TREM-1 and TLR4 antagonism inhibits inflammation and thus
prevents maturation failure of AVF by reducing the development of intimal hyperplasia and vascular
remodeling primarily due to inflammatory cells, cathepsin L, IL-8 and MMP-12. These studies will be
performed in the blood and isolated VSMCs of femoral artery and femoral vein of the pigs from Aim 1.
Mechanistic studies will examine the effect of TREM-1 and TLR4 inhibition in the presence of IL-8 on neutrophils,
monocyte-differentiated macrophages and VSMCs, and cathepsin L-mediated elastin and collagen degradation
in VSMCs, and the effect of elastin-derived peptides on monocyte differentiation into macrophages and VSMC
proliferation and migration. Additional mechanistic studies will include the link between TLR4 and TREM-1 in
promoting matrix remodeling, release of inflammatory cytokines from neutrophils and macrophages in the cross-
talk inducing phenotype switch in VSMCs and macrophage polarization.
The findings from this study will confirm if TREM-1 is a novel target for therapeutic intervention and extend
the knowledge to develop better molecules to antagonize TREM-1 and design phase I clinical trials.
摘要
项目成果
期刊论文数量(27)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Barriers to the Cervical Cancer Screening by CPC-28 Questionnaire: A Pilot Study.
- DOI:10.26502/acbr.50170289
- 发表时间:2022
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- 影响因子:0
- 作者:
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Perspectives of Hospitalists in an Academic Health System.
- DOI:10.26502/aimr.0139
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:Clarke TR;Laban J;Luqman A
- 通讯作者:Luqman A
Assessing Pediatric Inter-Hospital Transfer: A single-center, Retrospective, Observational Study of Saudi Arabia's National Life-Saving Protocol.
评估小儿院间转移:对沙特阿拉伯国家挽救生命方案的单一中心,回顾性,观察性研究。
- DOI:10.26502/jppch.74050130
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Anatomical Injury Clusters in Polytrauma Patients.
- DOI:10.26502/jsr.10020270
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
A Case of Multidisciplinary Approach to Post-Radiotherapy Dilative Cardiomyopathy Undergoing Elective Cesarean Delivery: Anesthetic and Intensive Care Management.
- DOI:10.26502/fccm.92920288
- 发表时间:2022
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
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Devendra K. Agrawal其他文献
Environmental Influences on Atopic Eczema
环境对特应性湿疹的影响
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:0
- 作者:
Wismmy Lee;Fihr Chaudhary;Devendra K. Agrawal - 通讯作者:
Devendra K. Agrawal
Delivery of viral vectors for gene therapy in intimal hyperplasia and restenosis in atherosclerotic swine
- DOI:
10.1007/s13346-017-0409-0 - 发表时间:
2017-07-13 - 期刊:
- 影响因子:5.500
- 作者:
Sannette Hall;Devendra K. Agrawal - 通讯作者:
Devendra K. Agrawal
14-3-3ζ: an optimal housekeeping protein for western blot analysis in swine rotator cuff tendon studies
- DOI:
10.1007/s11010-025-05255-6 - 发表时间:
2025-03-23 - 期刊:
- 影响因子:3.700
- 作者:
Resmi Rajalekshmi;Vikrant Rai;Devendra K. Agrawal - 通讯作者:
Devendra K. Agrawal
Role of fibroblast plasticity and heterogeneity in modulating angiogenesis and healing in the diabetic foot ulcer
- DOI:
10.1007/s11033-022-08107-4 - 发表时间:
2022-12-17 - 期刊:
- 影响因子:2.800
- 作者:
Vikrant Rai;Rebecca Moellmer;Devendra K. Agrawal - 通讯作者:
Devendra K. Agrawal
Altered Vascular Extracellular Matrix in the Pathogenesis of Atherosclerosis
- DOI:
10.1007/s12265-020-10091-8 - 发表时间:
2021-01-08 - 期刊:
- 影响因子:2.500
- 作者:
Rohit Mohindra;Devendra K. Agrawal;Finosh G. Thankam - 通讯作者:
Finosh G. Thankam
Devendra K. Agrawal的其他文献
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{{ truncateString('Devendra K. Agrawal', 18)}}的其他基金
Novel Molecular Target to Prevent Maturation Failure of Arteriovenous Fistula
预防动静脉瘘成熟失败的新分子靶点
- 批准号:
10221042 - 财政年份:2019
- 资助金额:
$ 70.5万 - 项目类别:
Novel Approach to Stabilize Atherosclerotic Plaque in Carotid Artery
稳定颈动脉粥样硬化斑块的新方法
- 批准号:
9920604 - 财政年份:2018
- 资助金额:
$ 70.5万 - 项目类别:
GENE AND STEM CELL THERAPY IN CORONARY ARTERY BYPASS GRAFT
冠状动脉搭桥术中的基因和干细胞治疗
- 批准号:
9234420 - 财政年份:2015
- 资助金额:
$ 70.5万 - 项目类别:
GENE AND STEM CELL THERAPY IN CORONARY ARTERY BYPASS GRAFT
冠状动脉搭桥术中的基因和干细胞治疗
- 批准号:
8913536 - 财政年份:2015
- 资助金额:
$ 70.5万 - 项目类别:
EPICARDIAL ADIPOSE TISSUE, OBESITY AND INFLAMMATION IN ATHEROSCLEROSIS
动脉粥样硬化中的心外膜脂肪组织、肥胖和炎症
- 批准号:
8775002 - 财政年份:2014
- 资助金额:
$ 70.5万 - 项目类别:
EPICARDIAL ADIPOSE TISSUE, OBESITY AND INFLAMMATION IN ATHEROSCLEROSIS
动脉粥样硬化中的心外膜脂肪组织、肥胖和炎症
- 批准号:
8600755 - 财政年份:2013
- 资助金额:
$ 70.5万 - 项目类别:
EPICARDIAL ADIPOSE TISSUE, OBESITY AND INFLAMMATION IN ATHEROSCLEROSIS
动脉粥样硬化中的心外膜脂肪组织、肥胖和炎症
- 批准号:
9277559 - 财政年份:2013
- 资助金额:
$ 70.5万 - 项目类别:
EPICARDIAL ADIPOSE TISSUE, OBESITY AND INFLAMMATION IN ATHEROSCLEROSIS
动脉粥样硬化中的心外膜脂肪组织、肥胖和炎症
- 批准号:
8854138 - 财政年份:2013
- 资助金额:
$ 70.5万 - 项目类别:
EPICARDIAL ADIPOSE TISSUE, OBESITY AND INFLAMMATION IN ATHEROSCLEROSIS
动脉粥样硬化中的心外膜脂肪组织、肥胖和炎症
- 批准号:
8705012 - 财政年份:2013
- 资助金额:
$ 70.5万 - 项目类别:
VITAMIN D AND IMMUNOMODULATION IN CORONARY ARTERY DISEASE
冠状动脉疾病中的维生素 D 和免疫调节
- 批准号:
8703297 - 财政年份:2012
- 资助金额:
$ 70.5万 - 项目类别:
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