PHA Alfred P. Fishman Memorial Proof of Concept Research Grant Winner 2012

Michael Yeager, PhDMichael Yeager, PhD

Department of Pediatric Critical Care
Department of Bioengineering
University of Colorado Health Sciences Center, Denver, Denver, Colo.
Title: “Unfolded Protein Response Confers Apoptosis Resistance and Inflammation in Pulmonary Hypertension”
Term: December 1, 2012 through November 30, 2013

Summary of Research Project:

Pulmonary hypertension (PH) patients find it hard to breathe because the blood vessels in their lungs cannot get as much blood to their lungs. Part of the problem is that the cells around the blood vessels get too big, muscling off the vessels and making them smaller. We think we have found a reason why this happens and maybe even a way to stop them from damaging the lung vessels. Right now it appears that these pulmonary artery smooth muscle cells (PASMC) keep growing, do not die, and are the cause of the disease. We believe that because they do not die, the drugs we use to try to help PH patients don’t work. We think that these special muscle cells need to die off so that the blood vessels can stay open. Unfortunately, we do not yet know how they arise and what can be done to kill them, or if even killing them is a reasonably fruitful therapeutic goal.

The overall project goal is to better understand how PASMC become resistant to cell death in this disease, and how we
can possibly reverse the disease by rendering the cells susceptible to death. We will test our idea using cells from the lung blood vessels of experimental animals with PH. We will use two therapeutic approaches to reverse established PH in two rat models of PH.

The first will use salubrinal, a well-tolerated compound that regulates the unfolded protein response towards signaling pathways that lead to sensitivity to apoptosis. If this proves to reverse PH, then we aim to pursue additional studies using other compounds that act in a similar fashion. Similarly it is our assertion that histone deacetylase inhibitors (HDACi) will restore PASMC sensitivity to apoptosis invitro and in vivo. If true, then we hope to begin the process of exploring whether these compounds could be used in clinical trials.

We are very hopeful that the ideas we are testing will lead to new and better treatments for this disease. We believe that what we learn will directly improve the quality of life for PH patients. The successful completion of our work will yield the data needed to submit an R01 that seeks to study the role of the unfolded protein response in PH.