Richard Seonghun Nho, PhD

Assistant Professor of Medicine

Dr. Nho received his B.Sc from Yonsei University, Seoul, S. Korea and his PhD in Infectious Diseases from the University of Manchester, England.  

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
For a comprehensive listing of Dr. Nho's recent publications refer to PubMed, a service of the National Library of Medicine

• Xia H, Diebold D, Nho RS, Perlman 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. J Exp Med 2008, 205(7):1659-72. PMC: 2442643 PMCID: PMC2442643
• 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 O, Diebold D, Fan D,. Peterson M, Nho RS, Bitterman PB, Henke CA. Fibrotic fibroblasts manifest genome-wide derangements of translational control. PLoS ONE. 2008; 3(9): e3220. PMCID: PMC2528966.
• Nho RS, Kahm J, Xia H, Henke C. Aberrant FoxO3a function confers fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) with a hyper-proliferative and apoptotic-resistant phenotype. Am J Respir Crit Care Med. 2009; 179:A5620.
• Nho RS. FoxO3a function in cardiovascular diseases in patients with idiopathic pulmonary fibrosis (IPF). Arterioscler Thromb Vasc Biol 2009; 29:e120.
• Nho RS, Kahm J. Integrin-collagen interaction suppresses Fox03a by the coordination of Akt and PP2A. J Biol Chem. 2010; 285: 14195-209.
• Nho RS. Fox03a activity is aberrantly low in IPF fibroblasts on polymerized collagen matrix. Am J Respir Crit Care Med. 2010; 181:A3533.
• Xia H, Nho RS, Jessarun J, Kahm J, Henke CA. Low PP2A activity in IPF fibroblasts is associated with elevated level of inactive GSH-3β and increased nuclear β Catenin. Am J Respir Crit Care Med. 2010; 181:A3508.

Grant Support 

• American Lung Association of the Upper Midwest (07/01/08 - 6/30/11)
  Pulmonary Fibrosis Research Grant: A Pathological Integrin Growth-Signaling Pathway Regulates Aberrant IPF Fibroblast Proliferation on Extracellular Matrix. The objective of this ALA proposal is to examine the hypothesis that integrin-collagen interaction regulates eIF4E translational activity and fibroblast proliferation via modulation of 4EBP1 function.
  Role: Principal Investigator
• American Heart Association (07/01/08 - 06/30/11)
  Scientist Development Grant
  The objective of this proposal is to explore the role of integrin-ECM interaction in regulating the formation of a distinct integrin-signaling complex involving PP2A and its role in controlling fibroblast proliferation and viability.
  Role: Principal Investigator
• NIH/NHLBI R21 RHL096567A (7/1/2009 – 6/30/2011)
  Role of FoxO3a in Regulating the IPF Fibroblast Phenotype. The objective of this proposal is to examine the role of the FoxO3a transcriptional activator in regulating the IPF fibroblast phenotype.
  Role: Principal Investigator
• NIH RO1 HL089228-01A2 (4/1/2009 – 3/31/2014)
  The objective of this proposal is to define the role of integrin in regulating PTEN function in response to fibroblast interaction with polymerized type I collagen
  Role: Co-Investigator, PI: Craig Henke
• NIH/NHLBI PO1 HL091775 (4/1/2009 – 3/31/2014)
  The objective of this proposal is to provide direct mechanistic insight into the molecular processes that make an IPF fibroblast abnormal by uncovering those components of the myofibroblast cellular machinery that result in unrelenting fibrosis in IPF, and in proper tissue healing under normal circumstances.
  Role: Co-Investigator, PI: Craig Henke