Richard Nho, PhD

Assistant Professor of Medicine, Division of Pulmonary, Allergy, Critical Care and Sleep Medicine

Richard Nho

Contact Info

nhoxx002@umn.edu

Mailing Address:
Division of Pulmonary, Allergy, Critical Care and Sleep Medicine
420 Delaware Street SE
MMC 276 (Pulmonary)
MMC 434 (Allergy)
Minneapolis, MN 55455

Administrative Assistant Name
PACCS

Administrative Phone
612-624-0999

Administrative Email
paccmed@umn.edu

Administrative Fax Number
612-625-2174

PhD in Infectious Diseases, University of Manchester, England

Yonsei University, Seoul, S. Korea

Research

Research Summary/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.

Publications

  • Nho RS, Peterson M, Hergert P, Henke CA. FoxO3a (Forkhead Box O3a) deficiency protects Idiopathic Pulmonary Fibrosis (IPF) fibroblasts from type I polymerized collagen matrix-induced apoptosis via caveolin-1 (cav-1) and Fas. PLoS One. 2013 Apr 8;8(4):e61017.
  • Nho RS*, Polunovsky B. Translational control of the fibroblasts and extracellular matrix association: an application to pulmonary fibrosis. 2013, Translation. 1:1-7.
  • Xia H, Seeman J, Hong J, Buddi V, Jessurun J, Smith K, Nho RS, Kahm J, Henke CA. Pathologically low 1 integrin increases catenin function in IPF fibroblasts on collagen matrix. Am J Pathol. 2012. 181;222-33.
  • Horowitz JC, Ajayi IO, Kulasekaran P, Rogers DS, White JB, Townsend SK, White ES, Nho RS, Higgins PD, Huang SK, Sisson TH. Survivin expression induced by endothelin-1 promotes myofibroblast resistance to apoptosis. Int J Biochem Cell Biol. 2012 Jan;44(1):158-69.
  • Nho RS*, Hergert P, Kahm J, Jessurun J, Henke C. Pathological alteration of FoxO3a activity promotes idiopathic pulmonary fibrosis fibroblast proliferation on type I collagen matrix. Am J Pathol. 2011 Nov;179(5):2420-30.
  • Nho RS*, Peterson M. Eukaryotic translation initiation factor 4E binding protein 1 (4EBP-1) function is suppressed by Src and protein phosphatase 2A (PP2A) on extracellular matrix. J Biol Chem. 2011 Sep 16;286(37):31953-65.
  • Xia H, Nho RS, Jessarun J, Kahm J, Henke CA. Low PP2A activity in IPF fibroblasts is associated with elevated level of inactive GSH-3? and increased nuclear ? Catenin. Am J Respir Crit Care Med. 2010; 181:A3508.
  • 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. FoxO3a function in cardiovascular diseases in patients with idiopathic pulmonary fibrosis (IPF). Arterioscler Thromb Vasc Biol 2009; 29:e120.
  • 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.