Barbara D. Smith, PhD
Professor
Boston University School of Medicine
Dept of Biochemistry

PhD, Boston University
MS, Boston University



The primary goal in our laboratory is to establish a better understanding of the mechanisms involved in the control of collagen gene expression associated with inflammation, atherosclerosis, tumors, and fibrotic diseases including systemic sclerosis. Collagen, a family of extracellular proteins, plays a critical role in remodeling after injury. Progressive deposition of excess extracellular matrix (ECM), occurs in a large group of diseases with no effective therapy including cardiovascular disease, pulmonary fibrosis, diabetic nephropathy, systemic sclerosis, and liver cirrhosis. Fibrosis (excessive scarring) is a progressive deposition of excess collagen-rich extracellular matrix produced by activated myofibroblasts leading to impairment and finally failure of affected organs. In normal healing following injury, fibroblasts differentiate into myofibroblasts. If progression to fibrosis occurs, these myofibroblasts do not undergo apoptosis but instead continue to proliferate and produce excess amounts of ECM. Isolated primary fibroblasts from fibrotic lesions maintain their activated myofibroblast phenotype containing abundant stress fibers with smooth muscle actin (SMA). Myocardin related transcription factors (MRTF-A, MRTF-B), members of the myocardin family, link actin dynamics with gene transcription. Our data indicate that MRTF-A dramatically (100 fold) activates collagen transcription. Fibroblasts with knockdown of MRTFA have different morphology and produce less collagen and SMA. We hypothesize that MRTFA plays a central role in activation and perpetuation of myofibroblast during the development of fibrotic disease.

Our laboratory has been examining both activation and repression of collagen transcription using molecular biology approaches. We have demonstrated that collagen type I genes are methylated in the first exon in cancer cells and colon cancer. Collagen gene is silenced in certain tumors. A methylation sensitive DNA binding protein (RFX1) represses transcription by binding to the collagen gene transcription start site. This protein belongs to a family of proteins that can function as transcription activators or repressors. RFX1 interacts with a co-repressor complex containing histone deacetylase which could be involved with spreading of DNA methylation and silencing. A RFX5 complex containing three other proteins (RFXANK/B, RFXAP, CIITA) are essential activators of major histocompatibility complex class II (MHC II) proteins that respond to interferon-gamma during inflammation and activate cells to become antigen producing cells. Interferon activates RFX5/CIITA synthesis and nuclear localization in human fibroblasts and smooth muscle cells. RFX5 proteins form a complex at the RFX site at the collagen gene transcription start site and recruits CIITA to repress collagen transcription through a phosphorylation sensitive interaction with co-repressor complex. Thus, this family of proteins may be very important modulators of collagen expression during inflammation.

Graduate Faculty (Primary Mentor of Grad Students)
Boston University School of Medicine, Division of Graduate Medical Sciences




Collagen Regulation in Systemic Sclerosis
01/15/2012 - 12/31/2013 (PI)
Scleroderma Foundation

The Role of the Arterial Wall in Atherosclerosis
09/01/1976 - 08/31/2009 (Co-PI)
NIH/National Heart, Lung, and Blood Institute
5 P01 HL13262 34

Post-Translational Modifications of RFX5 and CIITA in Collagen Repression During Artherosclerotic Injury
07/01/2005 - 06/30/2007 (Dept Sponsor)
American Heart Association

Pathogenic Mechanisms of Venous Disease
05/01/2000 - 04/30/2005 (PI)
Roger Williams Hospital NIH NCI

Collagen Gene Expression and Atherosclerosis
05/01/2003 - 09/30/2003 (PI)
NIH/National Heart, Lung, and Blood Institute
1 R01 HL72996 01




Yr Title Project-Sub Proj Pubs
2009 Collagen Transcription and Lung Fibrosis 5R01HL068094-09 14
2008 Collagen Transcription and Lung Fibrosis 5R01HL068094-08 14
2007 Collagen Transcription and Lung Fibrosis 5R01HL068094-07 14
2006 Collagen Transcription and Lung Fibrosis 5R01HL068094-06 14
2005 Collagen Transcription and Lung Fibrosis 2R01HL068094-05A1 14
2004 Collagen transcription and lung fibrosis 5R01HL068094-04 14
2003 Collagen Gene Expression and Atherosclerosis 2P01HL013262-30A1-38 162
2003 Collagen Gene Expression and Atherosclerosis 1R01HL072996-01 1
2003 Collagen transcription and lung fibrosis 5R01HL068094-03 14
2002 Collagen transcription and lung fibrosis 5R01HL068094-02 14
Showing 10 of 30 results. Show All Results
Publications listed below are automatically derived from MEDLINE/PubMed and other sources, which might result in incorrect or missing publications. Faculty can login to make corrections and additions.

  1. Shiwen X, Stratton R, Nikitorowicz-Buniak J, Ahmed-Abdi B, Ponticos M, Denton C, Abraham D, Takahashi A, Suki B, Layne MD, Lafyatis R, Smith BD. A Role of Myocardin Related Transcription Factor-A (MRTF-A) in Scleroderma Related Fibrosis. PLoS One. 2015; 10(5):e0126015.View Related Profiles. PMID: 25955164; PMCID: PMC4425676; DOI: 10.1371/journal.pone.0126015;.
  2. McDonald ME, Li C, Bian H, Smith BD, Layne MD, Farmer SR. Myocardin-related transcription factor A regulates conversion of progenitors to beige adipocytes. Cell. 2015 Jan 15; 160(1-2):105-18.View Related Profiles. PMID: 25579684; PMCID: PMC4384505; DOI: 10.1016/j.cell.2014.12.005;.
  3. Ponticos, M., and B.D. Smith. Journal of biomedical research. Extracellular matrix synthesis in vascular disease: hypertension, and atherosclerosis. 2014; 28(1):25-39..
  4. Tumelty KE, Smith BD, Nugent MA, Layne MD. Aortic carboxypeptidase-like protein (ACLP) enhances lung myofibroblast differentiation through transforming growth factor ß receptor-dependent and -independent pathways. J Biol Chem. 2014 Jan 31; 289(5):2526-36.View Related Profiles. PMID: 24344132; PMCID: PMC3908388; DOI: 10.1074/jbc.M113.502617;.
  5. Ponticos M, Smith BD. Extracellular matrix synthesis in vascular disease: hypertension, and atherosclerosis. J Biomed Res. 2014 Jan; 28(1):25-39. PMID: 24474961; DOI: 10.7555/JBR.27.20130064;.
  6. Luchsinger LL, Patenaude CA, Smith BD, Layne MD. Myocardin-related transcription factor-A complexes activate type I collagen expression in lung fibroblasts. J Biol Chem. 2011 Dec 23; 286(51):44116-25.View Related Profiles. PMID: 22049076; PMCID: PMC3243519; DOI: 10.1074/jbc.M111.276931;.
  7. Xu Y, Luchsinger L, Lucey EC, Smith BD. The effect of class II transactivator mutations on bleomycin-induced lung inflammation and fibrosis. Am J Respir Cell Mol Biol. 2011 Jun; 44(6):898-905. PMID: 20705943; PMCID: PMC3135849; DOI: 10.1165/rcmb.2009-0416OC;.
  8. Wu X, Kong X, Luchsinger L, Smith BD, Xu Y. Regulating the activity of class II transactivator by posttranslational modifications: exploring the possibilities. Mol Cell Biol. 2009 Nov; 29(21):5639-44. PMID: 19720744; PMCID: PMC2772741; DOI: 10.1128/MCB.00661-09;.
  9. St Hilaire C, Koupenova M, Carroll SH, Smith BD, Ravid K. TNF-alpha upregulates the A2B adenosine receptor gene: The role of NAD(P)H oxidase 4. Biochem Biophys Res Commun. 2008 Oct 24; 375(3):292-6.View Related Profiles. PMID: 18647598; PMCID: PMC2583397; DOI: 10.1016/j.bbrc.2008.07.059;.
  10. Xu Y, Ravid K, Smith BD. Major histocompatibility class II transactivator expression in smooth muscle cells from A2b adenosine receptor knock-out mice: cross-talk between the adenosine and interferon-gamma signaling. J Biol Chem. 2008 May 23; 283(21):14213-20.View Related Profiles. PMID: 18359773; PMCID: PMC2386913; DOI: 10.1074/jbc.M708657200;.
Showing 10 of 64 results. Show More

This graph shows the total number of publications by year, by first, middle/unknown, or last author.

Bar chart showing 55 publications over 31 distinct years, with a maximum of 3 publications in 1983 and 1984 and 1988 and 1989 and 1998 and 2006

YearPublications
19801
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19833
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72 E. Concord St Silvio Conte (K)
Boston MA 02118
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