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Principal Investigator: Alan Dardik
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $742,551
Funding agency: National Heart Lung and Blood Institute
The preferred vascular access for hemodialysis uses an arteriovenous fistula (AVF) to increase blood
flow through a vein. Successful adaptation of the venous conduit to the arterial-like fistula 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 increase successful clinical use of venous conduits.
During the funding period, we used an innovative mouse AVF model to show that TGF-β signaling
regulates venous adaptive remodeling to improve AVF patency; activation of both the smad2/3 (canonical) and
tak1 (noncanonical) pathways regulate venous remodeling; and endothelial cell-targeted TGF-β inhibition
regulates both collagen density and smooth muscle cell proliferation to improve AVF patency. We present
exciting new data that: 1) expression of the matricellular protein tenascin-C (TnC) is greatly increased and
colocalizes with the remodeling venous wall; 2) TnC regulates AVF patency and TGF-β signaling during
venous remodeling; 3) TnC expression is not downregulated in failed AVF; and 4) TnC knockout mice have
altered proportions of immune cells in the AVF wall. In addition, we have developed the mouse model further to
incorporate chronic kidney disease (CKD) via 5/6-nephrectomy and these AVF faithfully recapitulate human
AVF maturation. We hypothesize that modulating tenascin-C activity will alter venous remodeling, thereby
improving AVF maturation and patency. We will use our translationally relevant in vivo model, an innovative
tool using nanoparticles for local drug delivery, innovative methodology to analyze the 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 sex differences in TnC expression during human AVF remodeling in vivo. Aim II: Determine
whether TnC function mediates venous remodeling in mice with CKD. Aim III: Determine whether regulation of
immune cells is a mechanism of TnC-mediated venous remodeling.
A successful outcome of this investigation will have lasting impact by establishing whether TnC
mediates venous remodeling, and thus whether regulating TnC activity is a valuable strategy for clinical
translation to enhance AVF maturation. We will also determine whether reduced AVF maturation in women is
due to sex differences in TnC function as well as in inflammation and/or immunity. We use an innovative
strategy and novel tools and models to alter venous remodeling and thereby improve AVF maturation.
Terms: <AV fistula><Address><Arteriovenous Aneurysm><Arteriovenous fistula><Biology><Blood Vessels><Blood flow><Bone-Derived Transforming Growth Factor><Cell Body><Cell Communication and Signaling><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Signaling><Cell-Extracellular Matrix><Cells><Cellular Proliferation><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinical><Clinical Trials><Collagen><Cytotacin><Cytotactin><Data><Deposit><Deposition><Differences between sexes><Differs between sexes><Drugs><ECM><ESRD><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><Endothelial Cells><Environment><Expenditure><Extracellular Matrix><Failure><Female><Fistula><Funding><Goals><Healthcare><Hemodialyses><Hemodialysis><Hexabrachion><Human><Hyperplasia><Hyperplastic><Immune><Immunes><Immunity><Immunomodulation><Inflammation><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Investigation><KO mice><Knock-out Mice><Knockout Mice><Knowledge><Legal patent><Leiomyocyte><Macrophage><Mechanics><Mediating><Mediator><Medication><Methodology><Mice><Mice Mammals><Milk Growth Factor><Modeling><Modern Man><Murine><Mus><Mφ><Needles><Nephrectomy><Null Mouse><Operative Procedures><Operative Surgical Procedures><Outcome><Patents><Pathway interactions><Patients><Pharmaceutical Preparations><Physiology><Platelet Transforming Growth Factor><Procedures><Proteins><Puncture procedure><Punctures><Research Resources><Research Specimen><Resources><Sex Differences><Sexual differences><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Specimen><Surgical><Surgical Interventions><Surgical Procedure><T-Cell Subsets><T-Lymphocyte Subsets><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><Techniques><Tenascin><Tenascin-C><Testing><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Veins><Venous><Wild Type Mouse><Woman><Work><biological signal transduction><chronic kidney disease><clinical translation><clinically translatable><density><drug/agent><experience><health care><hemodynamics><human disease><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><improved><in vivo><in vivo Model><innovate><innovation><innovative><interventional strategy><local drug delivery><male><mechanic><mechanical><men><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><new approaches><next generation><novel><novel approaches><novel strategies><novel strategy><pathway><sex based differences><sex-dependent differences><sex-related differences><sex-specific differences><shear stress><surgery><tool><transcriptomics><vascular><wildtype mouse>