The applicant is committed to developing a career as a successful physician-scientist and has created a career development plan described in this proposal that will allow him to do so. The central component of this five-year plan is the research project outlined below. In addition, the applicant will benefit from the mentorship of Dr. Marc Peters-Golden (primary) and Dr. Bruce Richardson (co-mentor), both accomplished senior professors with extensive and successful track records for mentoring. Formal coursework, seminars, and conference participation are included in this plan. This plan is further enhanced by the outstanding research and mentoring environment that exists at the University of Michigan. Idiopathic pulmonary fibrosis (IPF) is a devastating disease with limited effective therapies. Abnormal fibroproliferation is a key pathobiological hallmark. Prostaglandin (PG) E2 is a lipid mediator that potently inhibits fibroblasts, the main effector cell in fibrotic responses. The applicant has recently discovered that fibroblasts from some patients with IPF are resistant to PGE2 suppression, and that this is due to deficiency of the E prostanoid (EP) 2 receptor. This finding parallels observations made in the bleomycin mouse model of pulmonary fibrosis. What is unclear is how EP2 expression is lost in these cells. Epigenetic changes, which are covalent modifications to DMA and chromatin, are important in regulating gene expression, and are increasingly recognized to be important in disease. Preliminary data suggest that epigenetic mechanisms may be responsible for loss of EP2 expression and impaired PGE2 responsiveness in fibrotic fibroblasts. To test this hypothesis, we will study lung fibroblasts from cell lines, patients with DIP, and from mice treated with bleomycin.
Our Specific Aims will be to address the role of 1) DMA methylation and 2) histone deacetylation in regulating EP2 receptor expression and PGE2 responses in normal lung fibroblasts. We will then study how DMA methylation and/or histone deacetylation may be responsible for EP2 deficiency/PGE2 resistance in fibroblasts from 3) bleomycin-treated mice and 4) patients with IPF. The applicant will build upon his productive training experience by acquiring new scientific knowledge and research skills, particularly in the area of epigenetics, a field that has generated significant enthusiasm within the scientific community. Successful completion of the outlined studies will provide new insight into pathogenic mechanisms of pulmonary fibrosis and provide the applicant with the skills to achieve academic independence in an exciting and important research niche.

Public Health Relevance

Idiopathic pulmonary fibrosis is a devastating lung disease with a poor prognosis and little effective therapy. The research proposed in this plan seeks to better understand the pathogenesis of pulmonary fibrosis which may lead to the development of better therapeutic strategies against this deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HL094657-04
Application #
8241049
Study Section
Special Emphasis Panel (ZHL1-CSR-O (O1))
Program Officer
Colombini-Hatch, Sandra
Project Start
2009-04-01
Project End
2014-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
4
Fiscal Year
2012
Total Cost
$133,712
Indirect Cost
$9,712
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Domingo-Gonzalez, Racquel; Wilke, Carol A; Huang, Steven K et al. (2015) Transforming growth factor-? induces microRNA-29b to promote murine alveolar macrophage dysfunction after bone marrow transplantation. Am J Physiol Lung Cell Mol Physiol 308:L86-95
Huang, Steven K; Scruggs, Anne M; McEachin, Richard C et al. (2014) Lung fibroblasts from patients with idiopathic pulmonary fibrosis exhibit genome-wide differences in DNA methylation compared to fibroblasts from nonfibrotic lung. PLoS One 9:e107055
Penke, Loka R K; Huang, Steven K; White, Eric S et al. (2014) Prostaglandin E2 inhibits ?-smooth muscle actin transcription during myofibroblast differentiation via distinct mechanisms of modulation of serum response factor and myocardin-related transcription factor-A. J Biol Chem 289:17151-62
Garrison, Garth; Huang, Steven K; Okunishi, Katsuhide et al. (2013) Reversal of myofibroblast differentiation by prostaglandin E(2). Am J Respir Cell Mol Biol 48:550-8
Huang, S K; Scruggs, A M; Donaghy, J et al. (2013) Histone modifications are responsible for decreased Fas expression and apoptosis resistance in fibrotic lung fibroblasts. Cell Death Dis 4:e621
Domingo-Gonzalez, Racquel; Huang, Steven K; Laouar, Yasmina et al. (2012) COX-2 expression is upregulated by DNA hypomethylation after hematopoietic stem cell transplantation. J Immunol 189:4528-36
Sisson, Thomas H; Maher, Toby M; Ajayi, Iyabode O et al. (2012) Increased survivin expression contributes to apoptosis-resistance in IPF fibroblasts. Adv Biosci Biotechnol 3:657-664
Huang, Steven K; Scruggs, Anne M; Donaghy, Jake et al. (2012) Prostaglandin E? increases fibroblast gene-specific and global DNA methylation via increased DNA methyltransferase expression. FASEB J 26:3703-14
Horowitz, Jeffrey C; Ajayi, Iyabode O; Kulasekaran, Priya et al. (2012) Survivin expression induced by endothelin-1 promotes myofibroblast resistance to apoptosis. Int J Biochem Cell Biol 44:158-69

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