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Principal Investigator: PRABIR ROY-CHAUDHURY
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $523,728
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
ABSTRACT
Arteriovenous fistulae (AVF) are the preferred mode of permanent dialysis vascular access because of better
long-term survival and reduced infection risks as compared to dialysis grafts and catheters. Unfortunately, AVFs
have a maturation failure rate (defined as inadequate diameter and blood flow for dialysis) of over 50% at 6
months, which results in multiple additional interventions, and also a prolonged period of tunneled dialysis
catheter dependency with all of its attendant complications. Thus, AVF maturation failure results in a very
significant morbidity, mortality and economic cost.
We and others have previously demonstrated that AVF maturation failure occurs due to a peri-anastomotic
venous segment stenosis characterized by the de-differentiation of vascular smooth muscle cells (VSMC) into a
synthetic phenotype, which then results in an aggressive venous neointimal hyperplasia. We have also
developed a unique expertise both in the biology of AVF maturation (Roy-Chaudhury) and in the signal
transduction mechanisms involved in VSMC phenotypic switching (Xi). We now plan to apply this combined
experience and expertise to study the signal transduction pathways responsible for AVF maturation failure.
The overarching central hypothesis of this proposal, therefore, is that environmental modulation of the insulin
receptor substrate 1 (IRS-1) signal transduction pathway plays a key role in VSMC phenotype switching which
then results in neointimal hyperplasia and AVF maturation failure. We plan to address this central hypothesis
through three specific aims.
Specific Aim 1 will assess the impact of different combinations of hyperglycemia, uremia and genetic
manipulation of IRS-1 and Kruppel like factor 4 (KLF-4) on signal transduction/VSMC phenotypic switch
pathways using explanted venous (jugular) and arterial (carotid) VSMC from C57Bl/6 WT control mice. Specific
Aim 2 will assess the impact of this same upstream manipulation on signal transduction pathways, VSMC
phenotypic switch and clinical, hemodynamic and histological endpoints, in a validated mouse model of AVF
stenosis at 2, 7 and 14 days, post-surgery. Finally, Specific Aim 3 will assess the impact of nutlin-3, an inhibitor
of MDM2 mediated ubiquitination of p-53 (which inhibits VSMC phenotypic switching) on the in-vitro and in-vivo
end points described in Specific Aims 1 and 2 respectively.
If successful, this novel, innovative, mechanism driven and pre-emptive approach to the intractable problem of
AVF maturation failure, could significantly reduce the clinical morbidity and economic cost associated with this
unmet clinical need.
Terms: <AV fistula><Address><Antiheparin Factor><Antioncogene Protein p53><Area><Arteriovenous Aneurysm><Arteriovenous fistula><Basal Transcription Factor><Basal transcription factor genes><Biology><Blood Platelet Factor IV><Blood Vessels><Blood flow><Blood platelet factor 4><Catheters><Cell Communication and Signaling><Cell Signaling><Cellular Expansion><Cellular Growth><Cellular Tumor Antigen P53><Chemokine (C-X-C motif) Ligand 4><Clinical><Coronary><Country><Dependence><Diabetes Mellitus><Dialysis><Dialysis procedure><Diameter><Dilatation><Dilatation - action><Dysfunction><EZF protein><Ecological impact><Environmental Impact><Experimental Models><Extremities><Factor 4><Failure><Functional disorder><Future><GKLF protein><General Population><General Public><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genetic><Goals><Growth><Growth Agents><Growth Factor><Growth Substances><HDM2><Hemodialyses><Hemodialysis><Heparin Neutralizing Protein><Histologic><Histologically><Humulin R><Hyperglycemia><Hyperplasia><Hyperplastic><IRS-1 protein><In Vitro><Infection><Insulin><Insulin Receptor Substrate 1><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Klf4 protein><Knock-out><Knockout><Kruppel-like factor 4><Leiomyocyte><Limb structure><Limbs><MDM2><MDM2 gene><MDMX protein><Mdm-2 protein><Mediating><Mice><Mice Mammals><Morbidity><Morbidity - disease rate><Murine><Mus><Non-Trunk><Novolin R><Oncoprotein MDM2><Oncoprotein p53><P53><PF4 Gene><Pathologic Constriction><Pathological Constriction><Pathway interactions><Patients><Peripheral Angiopathies><Peripheral Vascular Diseases><Peripheral Vascular Disorder><Phenotype><Phosphoprotein P53><Phosphoprotein pp53><Physiopathology><Platelet Factor 4><Play><Protein TP53><Proteins Growth Factors><Recombinant Platelet Factor 4><Regular Insulin><Role><SCYB4><Signal Transduction><Signal Transduction Pathway><Signal Transduction Systems><Signaling><Small Inducible Cytokine B4><Small Inducible Cytokine Subfamily B, Member 4><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Stenosis><TP53><TP53 gene><TRP53><Tissue Growth><Transcription Factor Proto-Oncogene><Transcription factor genes><Tumor Protein p53><Tumor Protein p53 Gene><Ubiquitilation><Ubiquitination><Ubiquitinoylation><Uremia><Vascular Smooth Muscle><Venous><biological signal transduction><cell growth><diabetes><dialysis therapy><economic cost><epithelial zinc finger protein><experience><gamma-Thromboglobulin><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><gut-enriched Kruppel-like factor><hemodynamics><hyperglycemic><in vivo><infection risk><inhibitor><innovate><innovation><innovative><insulin receptor substrate 1 protein><interventional strategy><mdm-2 oncogene protein><mdm2 protein><mortality><mouse model><murine model><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><nutlin 3><ontogeny><overexpress><overexpression><p53 Antigen><p53 Genes><p53 Tumor Suppressor><p53-Binding Protein MDM2><pathophysiology><pathway><peripheral blood vessel disorder><platelet factor IV><protein p53><shear stress><social role><transcription factor><ubiquination><ubiquitin conjugation><uremia of renal origin><vascular>