Adaptive immunity regulates arteriovenous fistula remodeling
适应性免疫调节动静脉内瘘重塑
基本信息
- 批准号:10574913
- 负责人:
- 金额:$ 77.13万
- 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:2022-12-12 至 2026-11-30
- 项目状态:未结题
- 来源:
- 关键词:AddressAffectAgeArteriovenous fistulaBiologyBlood VesselsBlood flowCell physiologyCellsChronic Kidney FailureClinicalClinical TrialsCyclosporineDataEncapsulatedEnd stage renal failureEnvironmentExpenditureFailureFemaleFistulaGonadal Steroid HormonesHealthcareHemodialysisHormonesHumanHyperplasiaImmuneImmune responseInnate Immune ResponseInterventionInvestigationKnowledgeLegal patentMacrophageMechanicsMediatingMethodologyModelingMusNeedlesNephrectomyOperative Surgical ProceduresOutcomePatientsPersonsPhysiologyPregnancyProceduresPuncture procedureResourcesRoleSex DifferencesSpecimenT cell therapyT-LymphocyteTechniquesTestingThickVein graftVeinsVenousWomanWorkadaptive immune responseadaptive immunityclinical translationexperiencehemodynamicshuman diseaseimprovedin vivoin vivo Modelinnovationlocal drug deliverymalemenmouse modelnanoparticlenext generationnovelnovel strategiesprogrammed cell death ligand 1responsesexual dimorphismshear stresstooltranscriptomics
项目摘要
The preferred vascular access for hemodialysis to treat end-stage renal disease involves using a vein
as a conduit to increase blood flow by surgically creating an arteriovenous fistula (AVF). Successful adaptation
of a venous conduit to the fistula or arterial environment requires remodeling of the vein wall without excessive
wall thickening, enabling mechanical strength to resist hemodialysis procedures that puncture the AVF wall
with large bore needles 3 times a week. However, the poor maturation and patency of AVF, especially in
women and requiring additional re-do procedures and surgery, reflects our imperfect understanding of the
biology of venous remodeling that leads to successful venous adaptation to the fistula environment. This
knowledge gap creates an unmet need for novel approaches to enhance venous remodeling and thereby to
increase successful clinical use of venous conduits.
Using a mouse AVF model that recapitulates human AVF maturation and shows sex differences, we
have shown that both an innate immune response as well as an adaptive immune response regulate venous
remodeling. We present exciting new data that sex hormones mediate sex differences in wall thickness during
venous remodeling. In addition, we have developed the mouse model further to incorporate chronic kidney
disease (CKD) via 5/6-nephrectomy; AVF in the CKD environment show altered venous remodeling compared
with control mice and these AVF faithfully recapitulate human AVF maturation. We hypothesize that since T
cells mediate venous remodeling, modulating adaptive immunity will alter venous remodeling, thereby
improving AVF patency and ultimately fistula utilization in human patients. We will use our translationally
relevant in vivo model, an innovative tool encapsulating cyclosporine in nanoparticles for local drug delivery,
innovative methodology to analyze the immune cell composition within the AVF wall, as well as advanced next-
generation analyses using transcriptomics techniques that are available at Yale, to test our innovative
hypothesis with the following specific aims:
Aim I: Determine whether sex differences in adaptive immunity between women and men affect AVF
remodeling in vivo. Aim II: Determine whether sex hormones mediate sex differences in the immune response
during AVF remodeling in mice with CKD. Aim III: Determine whether PD-L1 expression regulates the effects
of adaptive immunity on AVF remodeling in mice with CKD.
A successful outcome of this investigation will have lasting impact by establishing whether there is a T
cell basis underlying venous remodeling and thus manipulation of adaptive immunity is a valuable strategy for
clinical translation to enhance AVF patency. We will also determine whether reduced AVF maturation in
women is due to sex differences in adaptive immunity. We use an innovative strategy and novel tools and
models to manipulate adaptive immunity to alter venous remodeling and thereby improve AVF patency.
血液透析治疗终末期肾脏疾病的首选血管通路包括使用静脉
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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Alan Dardik其他文献
Alan Dardik的其他文献
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{{ truncateString('Alan Dardik', 18)}}的其他基金
Molecular control of vascular smooth muscle reprogramming in arteriovenous fistula maturation
动静脉内瘘成熟过程中血管平滑肌重编程的分子控制
- 批准号:
10735849 - 财政年份:2023
- 资助金额:
$ 77.13万 - 项目类别:
Manipulating the matrix to improve arteriovenous fistula patency
操纵基质以改善动静脉内瘘的通畅
- 批准号:
10460349 - 财政年份:2019
- 资助金额:
$ 77.13万 - 项目类别:
Manipulating the matrix to improve arteriovenous fistula patency
操纵基质以改善动静脉内瘘的通畅
- 批准号:
10648012 - 财政年份:2019
- 资助金额:
$ 77.13万 - 项目类别:
Manipulating the matrix to improve arteriovenous fistula patency
操纵基质以改善动静脉内瘘的通畅
- 批准号:
10223421 - 财政年份:2019
- 资助金额:
$ 77.13万 - 项目类别:
Manipulating the matrix to improve arteriovenous fistula patency
操纵基质以改善动静脉内瘘的通畅
- 批准号:
9806370 - 财政年份:2019
- 资助金额:
$ 77.13万 - 项目类别:
Manipulating the matrix to improve arteriovenous fistula patency
操纵基质以改善动静脉内瘘的通畅
- 批准号:
10001593 - 财政年份:2019
- 资助金额:
$ 77.13万 - 项目类别:
Enhancing venous adaptation to the arterial environment
增强静脉对动脉环境的适应
- 批准号:
9243119 - 财政年份:2016
- 资助金额:
$ 77.13万 - 项目类别:
Enhancing venous adaptation to the arterial environment
增强静脉对动脉环境的适应
- 批准号:
9460535 - 财政年份:2016
- 资助金额:
$ 77.13万 - 项目类别:
Enhancing venous adaptation to the arterial environment
增强静脉对动脉环境的适应
- 批准号:
9102364 - 财政年份:2016
- 资助金额:
$ 77.13万 - 项目类别:
Molecular regulation of fistula adaptation for dialysis access
透析通路瘘管适应的分子调控
- 批准号:
8634237 - 财政年份:2014
- 资助金额:
$ 77.13万 - 项目类别:
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