Project description: More than 400,000 patients in the US have end stage renal disease (ESRD), a population expected to double in the next decade. The long term goal of this current proposal and research program is to improve the care of patients with ESRD, the vast majority of who use long-term hemodialysis as their mode of renal replacement therapy. These patients require highly functioning vascular access for optimal therapeutic adequacy. Hemodialysis vascular access failure is frequently from venous stenosis secondary to neointimal hyperplasia (VNH). Preliminary data from our studies indicate that several mechanisms may be responsible for VNH formation. These include: 1) Elevated hypoxia inducible factor-1 alpha (HIF-11) which then stimulates;2) Increased expression of vascular endothelial growth factor-A (VEGF-A) and its receptors;3) Increased expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 (gelatinases);and 4) Proliferation and migration of fibroblasts from the adventitia and media to the intima resulting in VNH formation. We have developed state- of-the art molecular reagents and validated mouse nephrectomy with arteriovenous fistula model (AVF) and a hypoxia fibroblast cell culture model. The in vitro and in vivo models and accompanying reagents allow us to rigorously test our Central Hypothesis: Venous neointimal hyperplasia occurs when increased HIF-11 stimulates adventitial fibroblasts to differentiate into myofibroblasts (1-SMA positive cells). Increased expression of HIF-11 regulated proteins including VEGF-A, MMP-2 and MMP-9 results in the proliferation and migration of myofibroblasts into the intima leading to the formation of VNH. To test our central hypothesis we have developed three specific aims: 1). Determine the temporal and spatial role(s) of VEGF-A in VNH. 2). Determine the role(s) and regulation of MMPs in VNH. 3). Determine if the molecular mechanism of hypoxia induced fibroblast to myofibroblast differentiation is mediated by the VEGF- A/MMP axes. Successful completion of these aims will allow us to ultimately translate therapies aimed at inhibiting VNH to clinical trials thereby improving patient outcomes using commercially available anti-VEGF-A antibodies (Avastin (Bevacizumab)) and MMP inhibitors (Simvastatin or Sirolimus) which can be delivered using catheter based technology.
Public Health Relevance Statement: More than 400,000 patients in the US have end stage renal disease (ESRD), a population expected to double in the next decade. The long term goal of this current proposal and research program is to improve the care of patients with ESRD, the vast majority of who use long-term hemodialysis as their mode of renal replacement therapy.
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|Brahmbhatt, Akshaar; Remuzzi, Andrea; Franzoni, Marco et al. (2016) The molecular mechanisms of hemodialysis vascular access failure. Kidney Int 89:303-16|
|Brahmbhatt, Akshaar; Misra, Sanjay (2016) Techniques in Vascular and Interventional Radiology Drug Delivery Technologies in the Superficial Femoral Artery. Tech Vasc Interv Radiol 19:145-52|
|Janardhanan, Rajiv; Yang, Binxia; Kilari, Sreenivasulu et al. (2016) The Role of Repeat Administration of Adventitial Delivery of Lentivirus-shRNA-Vegf-A in Arteriovenous Fistula to Prevent Venous Stenosis Formation. J Vasc Interv Radiol 27:576-83|
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|Lee, Timmy; Misra, Sanjay (2016) New Insights into Dialysis Vascular Access: Molecular Targets in Arteriovenous Fistula and Arteriovenous Graft Failure and Their Potential to Improve Vascular Access Outcomes. Clin J Am Soc Nephrol 11:1504-12|
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|Brahmbhatt, Akshaar; Misra, Sanjay (2016) The Biology of Hemodialysis Vascular Access Failure. Semin Intervent Radiol 33:15-20|
|Nethi, Susheel Kumar; Veeriah, Vimal; Barui, Ayan Kumar et al. (2015) Investigation of molecular mechanisms and regulatory pathways of pro-angiogenic nanorods. Nanoscale 7:9760-70|
|Patel, Manesh R; Conte, Michael S; Cutlip, Donald E et al. (2015) Evaluation and treatment of patients with lower extremity peripheral artery disease: consensus definitions from Peripheral Academic Research Consortium (PARC). J Am Coll Cardiol 65:931-41|
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