PHA Alfred P. Fishman Memorial Proof of Concept Research Grant Winner 2012
Michael 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.
NAME: Michael Yeager,PhD
POSITION TITLE: Assistant Professor, Department of Pediatric Critical Care, University of Colorado Denver Health Sciences Center, Denver, Colo.
|INSTITUTION AND LOCATION
||FIELD OF STUDY
|University of Colorado Health Sciences Center, Denver, Colo.
|Universitat Giessen, Giessen, Germany
|National Jewish Research & Medical Center
Positions and Employment
- 2011-present, Assistant Professor, Dept. of Pediatric Critical Care, University of Colorado Denver Health Sciences Center; Dept. of Bioengineering
- 2007-2010, Instructor, Dept. of Pediatric Critical Care, University of Colorado Health Sciences Center
- 2004-2009, Visiting Assistant Professor, Dept. of Biology, Metropolitan State College, Denver, Colorado
- 2004-2007, Adjunct Instructor of Biology, Science Departments, Metropolitan State College, Denver, Community College
of Aurora, Denver, Colorado
- 2003-2007, Ruth Kirchenstein Postdoctoral Fellow, Depts. of Medicine, National Jewish Hospital & Univ. of Colorado Health Sciences Center, Denver, Colorado
- 2-D Difference-In-Gel Electrophoresis (DIGE)
- Amersham/GE robotic workstations MALDI-TOF Mass Spectrometry
- HPLC protein separation/sample fractionation
- Protein identification/database searching
- Biomarker validation
- 2003, Postdoctoral Fellow, MedKlinik II, Justus Liebig University, Giessen, Germany
- Chromatin immunoprecipitation
- Sequence and expression cloning
- Supervised graduate student projects and training
- Instructor, Graduate School
Other Experience and Professional Memberships
- 2012-present, Member, North American Vascular Biology Organization
- 2012-present, Member, Pulmonary Vascular Research Institute
- 1999-present, Member, American Thoracic Society
- 1999-present, Member, American Heart Association
- 1999-present, Member, European Respiratory Society
- 2011, The Children's Hospital Research Institute Research Scholar Award
- 2011, CCTSI Child Maternal Health Junior Pilot Award
- 2009, Actelion Pharmaceutical Young Investigators Award
- 2004-2008, Finalist, Faculty Senate Excellence in Teaching Award, Metropolitan State College, Denver, CO
- 2005, Finalist, Faculty of the Year, Community College of Aurora
- Yeager ME, Nega M, Belchenko DD, Colvin KL, Barajas CF, Cripe PJ, Stenmark KR. Expanded and active bronchus-associated lymphoid tissue in pulmonary artery hypertension associated with activating anti-fibroblast autoantibodies. Journal of Experimental Medicine. 2012 in review
- Yeager ME, Colvin KL, Everett A, Stenmark KR, Ivy DD. Plasma Proteomics of Differential Vasodilator Response in Pediatric Pulmonary Hypertension. Proteomics Clinical Applications. 2012 June 1 (ePub)
- Yeager ME, Reddy MB, Nguyen CM, Belchenko DD, Nega M, Yousefi M, Colvin KL, Loyd JE, Ivy DD, Stenmark KR. Activation of the Unfolded Protein Response is Associated with Pulmonary Artery Hypertension. Pulmonary Circulation. 2012 April-June: 2(2): 229-240.
- Cavasin MA, Demos-Davies K, Horn TR, Walker LA, Lemon DD, Birdsey N, Weiser-Evans MC, Harral J, Irwin DC, Anwar A, Yeager ME, Li M, Watson PA, Nemenoff RA, Buttrick PM, Stenmark KR, McKinsey TA. Selective class I histone deacetylase inhibition suppresses hypoxia-induced cardiopulmonary remodeling through an antiproliferative mechanism. Circ Res. 2012 Mar 2;110(5):739-48.
- Stenmark KR, Frid MG, Yeager ME, Li M, Riddle S, McKinsey TA, El Kasmi KC. Targeting the adventitial microenvironment in pulmonary hypertension: A potential approach to therapy that considers epigenetic change. Pulm Circ. 2012 Jan-March: 2(1):3-14.
- Yeager ME, Nguyen CM, Belchenko DD, Colvin KL, Takatsuki S, Ivy DD, Stenmark KR. Myeloid Suppressor Cells are Increased and Activated in Children and Young Adults with Pulmonary Hypertension. Chest. 2012 Apr;141(4):944-52.
- Yeager ME, Nguyen CM, Belchenko DD, Colvin KL, Takatsuki S, Ivy DD, Stenmark KR. Circulating Fibrocytes are Increased in Children and Young Adults with Pulmonary Hypertension. Eur Resp J. 2012 Jan;39(1):104-11.
- Yeager ME, Belchenko DD, Nguyen CM, Colvin KL, Ivy DD, Stenmark KR. Endothelin-1, the Unfolded Protein Response, and Persistent Inflammation-Role of Pulmonary Artery Smooth Muscle Cells. Am J Respir Cell Mol Biol, 2012 Jan;46(1)14-22.
- Yeager ME, Frid MG, Stenmark KR. Progenitor Cells in Pulmonary Vascular Remodeling. Pulm Circ. 2011 Jan: 1(1) 3-16.
- Stenmark KR, Frid MG, Yeager ME. Fibrocytes: potential new therapeutic targets for pulmonary hypertension? Eur Respir J. 2010 Dec;36(6):1232-5.
- Ryu J, Vicencio AG, Yeager ME, Kashgarian M, Haddad GG, Eickelberg O. Differential expression of matrix metalloproteinases and their inhibitors in human and mouse lung development., Thromb Haemost. 2005 Jul;94(1):175-83.
- Richter A, Yeager ME, Zaiman A, Cool CD, Voelkel NF, Tuder RM. Impaired transforming growth factor-beta signaling in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004 Dec 15;170(12):1340-8. Epub 2004 Sep 10.
- Eickelberg O, Yeager ME, Grimminger F. The tantalizing triplet of pulmonary hypertension-BMP receptors, serotonin receptors, and angiopoietins. Cardiovasc Res. 2003 Dec 1;60(3):465-7.
- Cool CD, Rai PR, Yeager ME, Hernandez-Saavedra D, Serls AE, Bull TM, Geraci MW, Brown KK, Routes JM, Tuder RM, Voelkel NF. Expression of human herpesvirus 8 in primary pulmonary hypertension. N Engl J Med. 2003 Sep18;349(12):1113-22.
- Voelkel NF, Cool C, Taraceviene-Stewart L, Geraci MW, Yeager ME, Bull T, Kasper M, Tuder RM. Janus face of vascular endothelial growth factor: the obligatory survival factor for lung vascular endothelium controls precapillary artery remodeling in severe pulmonary hypertension. Crit Care Med. 2002 May;30(5 Suppl):S251-6.
- Yeager ME, Golpon HA, Voelkel NF, Tuder RM. Microsatellite mutational analysis of endothelial cells within plexiform lesions from patients with familial, pediatric, and sporadic pulmonary hypertension. Chest. 2002 Mar;121(3 Suppl):61S.
- Geraci MW, Gao B, Hoshikawa Y, Yeager ME, Tuder RM, Voelkel NF. Genomic approaches to research in pulmonary hypertension. Respir Res. 2001;2(4):210-5. Epub 2001 May 1.
- Tuder RM, Cool CD, Yeager ME, Taraseviciene-Stewart L, Bull TM, Voelkel NF. The pathobiology of pulmonary
hypertension. Endothelium. Clin Chest Med. 2001 Sep;22(3):405-18.
- Tuder RM, Yeager ME, Geraci M, Golpon HA, Voelkel NF. Severe pulmonary hypertension after the discovery of the familial primary pulmonary hypertension gene. Eur Respir J. 2001 Jun;17(6):1065-9.
- Geraci MW, Moore M, Gesell T, Yeager ME, Alger L, Golpon H, Gao B, Loyd JE, Tuder RM, Voelkel NF. Gene expression patterns in the lungs of patients with primary pulmonary hypertension: a gene microarray analysis. Circ Res. 2001 Mar 30;88(6):555-62.
- Yeager ME, Halley GR, Golpon HA, Voelkel NF, Tuder RM. Microsatellite instability of endothelial cell growth and
apoptosis genes within plexiform lesions in primary pulmonary hypertension. Circ Res. 2001 Jan 19;88(1):E2-E11.
Ongoing Research Support
The Children's Hospital Research Institute Research Scholar Award, 05/01/2011-05/1/2012;
Title: Circulating Immunomodulatory Cells and Persistent Inflammation in Pulmonary Artery Hypertension
CCTSI Child Maternal Health Junior Pilot Award, 02/01/2011-02/01/2012;
Title: Role of Fibrocytes and Myeloid Derived Suppressor Cells in Persistent Inflammation Associated with Pediatric Pulmonary Hypertension
Past Research Support
Actelion Pharmaceutical, Young Investigators Award Grant, 01/04/2010-12/31/2010;
Title: Circulating Mesenchymal Precursors in Severe PAH and the Role of Endothelin-1 in their Recruitment and Differentiation into Fibrocytes
Manuscripts: Circulating Fibrocytes Are Increased in Pediatric Pulmonary Hypertension, Eur. Resp. J. 2011; Circulating Myeloid Derived Suppressor Cells Are Increased and Activated in Pulmonary Hypertension, CHEST, 2011