Stokes, Alexander PhD, BSc, MSc

Research Overview

2011-2012 RMATRIX Collaboration Pilot Projects Program Awards

Project Description

Abstract

Protection from Cardiac Hypertrophy via Pharmacological Inhibition of the Ion Channel TRPV1

This project is a T1 translational research study, which addresses the regulation of cardiac hypertrophy and subsequent heart failure, building on our preliminary in vivo data showing that i) knockout of TRPV1 protects from cardiac hypertrophy and ii) that a drug antagonist of TRPV1 also protects the heart from cardiac hypertrophy. This drug is an excellent candidate for translation to the clinic, and here we propose a full characterization of its therapeutic potential across multiple dimensions of cardiac pathology. Cardiac pathologies carry a staggering medical and economic impact in the USA, especially in Hawaii where the mortality rate from heart disease in Native Hawaiians is estimated to be 44% higher than other U.S. races, and Hawaii ranks 49th among US states for quality of cardiovascular health. The staggering ethical, medical and economic impact of cardiac pathologies creates a compelling justification to study therapeutic targets such as TRPV1. Current literature implicates TRPV1 activation in several cardiovascular pathologies, and our data suggest that TRPV1 is a tractable target in development of cardiac hypertrophy and heart failure. Importantly, there is an extensive pharmacopeia of TRPV1 antagonists, several of which have already been evaluated in humans as analgesics. This creates the potential for .fast-tracking. of a TRPV1-based cardiac therapeutic to the clinic. Our preliminary data show that the knockout of the calcium channel TRPV1, or application of a small molecule TRPV1 antagonist, suppresses the rate of cardiac hypertrophy, fibrosis and apoptosis in the heart, preserving heart function in modeled pressure overload cardiac hypertrophy. This antagonist, and others like it, are excellent candidates for translation from in vitro/in vivo studies, through pharmacological characterization, towards and eventual Phase I trial. This T1 proposal seeks to develop our understanding of these antagonists further and characterize in detail their effects on the progression of cardiac hypertrophy, fibrosis and apoptosis. As we move forward into the assessment of these antagonists for translation to the clinic, it has become necessary to compliment our laboratory.s existing expertise in cell biology, molecular biology and in vivo systems with expertise in drug analysis. We have therefore entered into an interdisciplinary collaboration, where Dr. Abby Collier (JABSOM) can provide us with her expertise in pharmacological and toxicological approaches to the assessment of TRPV1 antagonists as potential cardiac therapeutics, a key step in translation to the clinic. The data generated from this proposal will translate our current studies into novel clinical paradigms for treatment of cardiac hypertrophy, using existing, clinically tested, TRPV1-directed therapeutics that were originally designed as analgesics.

Selected Publications

• Horton JS, Wakano CT, Speck M, Stokes AJ.
  Two-pore channel 1 interacts with citron kinase, regulating completion of cytokinesis.
  Channels (Austin) 2015 [more...]


• Greineisen WE, Speck M, Shimoda LM, Sung C, Phan N, Maaetoft-Udsen K, Stokes AJ, Turner H.
  Lipid body accumulation alters calcium signaling dynamics in immune cells.
  Cell Calcium 2014 [more...]


• Horton JS, Buckley CL, Alvarez EM, Schorlemmer A, Stokes AJ.
  The calcium release-activated calcium channel Orai1 represents a crucial component in hypertrophic compensation and the development of dilated cardiomyopathy.
  Channels (Austin) 2014 [more...]


• Horton JS, Stokes AJ.
  The transmembrane channel-like protein family and human papillomaviruses: Insights into epidermodysplasia verruciformis and progression to squamous cell carcinoma.
  Oncoimmunology 2014 [more...]


• Umemoto EY, Speck M, Shimoda LM, Kahue K, Sung C, Stokes AJ, Turner H.
  Single-walled carbon nanotube exposure induces membrane rearrangement and suppression of receptor-mediated signalling pathways in model mast cells.
  Toxicol Lett 2014 [more...]


• Horton JS, Buckley CL, Stokes AJ.
  Successful TRPV1 antagonist treatment for cardiac hypertrophy and heart failure in mice.
  Channels (Austin) 2013 [more...]


• Buckley CL, Stokes AJ.
  Corin-deficient W-sh mice poorly tolerate increased cardiac afterload.
  Regul Pept 2011 [more...]


• Buckley CL, Stokes AJ.
  Mice lacking functional TRPV1 are protected from pressure overload cardiac hypertrophy.
  Channels (Austin) 2011 [more...]


• Chang L, Yakupov R, Nakama H, Stokes B, Ernst T.
  Antiretroviral treatment is associated with increased attentional load-dependent brain activation in HIV patients.
  J Neuroimmune Pharmacol 2008 [more...]