Richard Seonghun Nho, PhD

Research Interests:

Our major research interest is to elucidate the mechanisms by which the extracellular matrix (ECM) regulates human lung fibroblast proliferation and viability, and to identify crucial pathways via integrins.  A pathologic integrin growth-signaling pathway is critical in understanding aberrant IPF (idiopathic pulmonary fibrosis) fibroblast proliferation on extracellular matrices. We have previously discovered that :1) IPF fibroblast proliferation on polymerized collagen is associated with inappropriately low PTEN/PI3K/Akt activity and enhanced eIF4E activity; 2) integrin/ECM interaction regulates the protein expression of two critical tumor suppressor proteins, PTEN and 4EBP-1.  PTEN is a major inhibitor of the PI3K/Akt growth signal pathway and 4EBP-1 is an inhibitor of cap-dependent translation, which is regulated by the PI3K/Akt/mTOR pathway. Given this evidence, we hypothesize that the regulation of PTEN and 4EBP-1 function in response to IPF fibroblast interaction with the ECM will be abnormal. We are currently investigating integrin-mediated abnormal growth/survival signaling pathways in IPF fibroblasts.  

In addition, in an effort to begin to define the IPF fibroblast phenotype, we performed a series of experiments to comprehensively analyze the flow of genetic information in IPF fibroblasts within a tissue-like environment.  Using this approach, we have identified keratin 18 as a gene that is highly transcribed in IPF fibroblasts but not in control fibroblasts. Western analysis has confirmed that keratin 18 protein is expressed in IPF fibroblasts but not in controls. This is particularly intriguing for the following reasons: 1) keratin 18 is an epithelial protein that forms intermediate filaments and maintains cytoskeletal integrity; 2) alterations in keratin 18 expression occur during epithelial to mesenchymal transition (EMT); 3) EMT is a central process associated with cancer progression; persistence of keratin 18 expression is a hallmark of cancer cells derived from various epithelia and correlates with invasiveness; 4) in hepatocytes, deregulation of keratin 18 expression results in a misfolded protein response and the formation of keratin aggregates (Mallory bodies) promoting cell death; and 5) altered keratin 18 expression has been implicated with hepatic fibrosis in humans. While it is unclear what the consequences of keratin 18 expression are in IPF fibroblasts, the implications of finding an epithelial protein expressed in IPF fibroblasts are clear and point towards EMT.  EMT has recently been identified as a potential important source of mesenchymal cells in IPF. We hypothesize that keratin 18 expression is a marker of epithelial/fibroblast differentiation in IPF and that altered keratin 18 expression disrupts critical cellular functions in alveolar epithelial cells and IPF fibroblasts that may lead to progressive fibrosis in IPF.  Studies are underway to elucidate the functional importance of keratin 18 in regulating IPF fibroblast migration, proliferation and viability.

Our long-term goal is to characterize the molecular processes underlying the pathological ability of IPF fibroblasts to elude the anti-proliferative effects of polymerized collagen and to translate this understanding into novel therapeutic strategies to limit fibrosis.

Selected Recent Publications:

Nho RS, Sheaff R.  p27 and cancer.  Prog Cell Cycle Res 2003; 5:249-59.

Xia H, Nho RS, Kahm J, Kleidon J, Henke CA.  Focal adhesion kinase is upstream of phosphatidylinositol 3-kinase/Akt in regulating fibroblast survival in response to contraction of type I collagen matrices via a beta 1 integrin viability signaling pathway.  J Biol Chem  2004, 279:33024-34.

Nho RS, Xia H, Kahm J, Kleidon J, Diebold D, Henke CA.  Role of integrin-linked kinase in regulating phosphorylation of Akt and fibroblast survival in type I collagen matrices through a beta 1 integrin viability signaling pathway.  J Biol Chem 2005, 280:26630-9.

 Nho RS, Xia H, Kahm J, Kleidon J, Diebold D, Henke CA. PTEN regulates fibroblast elimination during collagen matrix contraction.  J Biol Chem 2006, 281:33291-301 

 Xia H, Diebold D, Nho RS, Perman D, Kahm J, Kleidon J, Avdulor A, Peterson M, Bitterman PB, Henke CA. Pathological integrin signaling enhances proliferation of primary lung fibroblasts  from patients' idiopathic pulmonary fibrosis. 2008,  J Exp Med 2008, 205(7):1659-72.

 Xia H, Nho RS, Kleidon J, Kahm J, Henke CA. Polymerized collagen inhibits fibroblast proliferation via a mechanism involving the formation of a Beta 1 integrin/PP2A/TSC2 complex that suppresses S6K1 activity.  J Biol Chem 2008, 283(29): 20350-60. 

Larsson Ola, Diebold D, Fan D, Peterson M, Nho RS, Bitterman PB, Henke CA. Fibrotic fibroblasts manifest genome-wide derangements of translational control.  PLoS Medicine 2008, accepted.

Grant Support

NIH R01 HL 074882 (07/01/05-06/30/09)
NIH/NHLBL
Extracellular Matrix Regulation of Fibroblast Viability
Role : Co-Investigator   PI : Craig Henke

American Lung Association of the Upper Midwest (07/01/08 - 6/30/10)
Pulmonary Fibrosis Research Grant
A Pathological Integrin Growth-Signaling Pathway Regulates Aberrant IPF Fibroblast Proliferation on Extracellular Matrix
Role : Principal Investigator

American Heart Association  (07/01/08 - 06/30/11)
Scientist Development Grant
Role : Principal Investigator

Last revised 8/24/2008