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Research Associate

Specialty Areas:

Genetic Analysis of Cystic Fibrosis Patients with Severe Liver Disease (CFLD)


BS, Northern Illinois University, 1992; MS, Northern Illinois University, 1994; PhD, Loyola University Medical Center, 1999; Postdoctoral fellow, University of North Carolina at Chapel Hill, Cystic Fibrosis Research Center, 1999-2001; Research Associate Scientist, University of North Carolina at Chapel Hill, Cystic Fibrosis Research Center, 2002-present.

Research Focus:

Only a subset of cystic fibrosis (CF) patients develop severe liver disease (biliary cirrhosis with portal hypertension; CFLD), and thisdoes not correlate with the type of CF gene (CFTR) mutation. Thus, there must be other (non-CFTR) genetic variation that contributes to the development of CFLD. The goals of our research are to study candidate genes that might modify CF liver disease, analyze genome-wide association study (GWAS) of 570,000 genetic markers (SNPs) in patients with CFLD, enroll additional patients with CFLD, and perform another GWAS in additional patients with CFLD. The long term goal of our research is to identify the major gene modifiers for CFLD, which will provide the opportunity for a novel, genetic-based technique to identify CF children at risk for CFLD. If successful, our study will provide novel prognostic approaches, and identification of novel, targeted therapies to prevent severe biliary cirrhosis before it occurs in CF children.

Overview of Scientific Contributions

Selected Bibliography:

  1. Stonebraker JR, Pace RG, Gallins PJ, Dang H, Aksit MA, Faino AV, Gordon WW, MacParland S, Bamshad MJ, Gibson RL, Cutting GR, Durie PR, Wright FA, Zhou YH, Blackman SM, O’Neal WK, Ling SC, Knowles MR. Genetic variation in severe cystic fibrosis liver disease is associated with novel mechanisms for disease pathogenesis. Hepatology. 2024 Mar 27. doi: 10.1097/HEP.0000000000000863. Epub ahead of print. PMID: 38536042.
  2. Shapiro AJ, Stonebraker JR, Knowles MR, Zariwala MA. A Deep Intronic, Pathogenic Variant in DNAH11 Causes Primary Ciliary Dyskinesia. Am J Respir Cell Mol Biol. 2022 Oct;67(4):511-514. doi: 10.1165/rcmb.2022-0176LE. PMID: 36178856. PMCID: PMC9648669.
  3. Shapiro AJ, Kaspy K, Daniels MLA, Stonebraker JR, Nguyen VH, Joyal L, Knowles MR, Zariwala MA. Autosomal dominant variants in FOXJ1 causing primary ciliary dyskinesia in two patients with obstructive hydrocephalus. Mol Genet Genomic Med. 2021 Jul;9(7):e1726. doi: 10.1002/mgg3.1726. PMID: 34132502; PMCID: PMC8372090.
  4. Dang H, Polineni D, Pace RG, Stonebraker JR, Corvol H, Cutting GR, Drumm ML, Strug LJ, O’Neal WK, Knowles MR. Mining GWAS and eQTL data for CF lung disease modifiers by gene expression imputation. PLoS One. 2020 Nov 30;15(11):e0239189. doi: 10.1371/journal.pone.0239189. PMID: 33253230. PMCID: PMC7703903.
  5. Polineni D, Piccorelli AV, Hannah WB, Dalrymple SN, Pace RG, Durie PR, Ling SC, Knowles MR, Stonebraker JR. Analysis of a large cohort of cystic fibrosis patients with severe liver disease indicates lung function decline does not significantly differ from that of the general cystic fibrosis population. PLoS One. 2018 Oct 11;13(10):e0205257. doi: 10.1371/journal.pone.0205257. PMID: 30307979. PMCID: PMC6181334.
  6. Rowson-Hodel AR, Wald JH, Hatakeyama J, O’Neal WK, Stonebraker JR, VanderVorst K, Saldana MJ, Borowsky AD, Sweeney C, Carraway KL Rd. Membrane Mucin Muc4 promotes blood cell association with tumor cells and mediates efficient metastasis in a mouse model of breast cancer. Oncogene. 2018 Jan 11;37(2):197-207. doi: 10.1038/onc.2017.327. PMID: 28892049. PMCID: PMC5930013.
  7. Polineni D, Dang H, Gallins PJ, Jones LC, Pace RG, Stonebraker JR, Commander LA, Krenicky JE, Zhou YH, Corvol H, Cutting GR, Drumm ML, Strug LJ, Boyle MP, Durie PR, Chmiel JF, Zou F, Wright FA, O’Neal WK, Knowles MR. Airway mucosal host defense is key to genomic regulation of cystic fibrosis lung disease severity. Am J Respir Crit Care Med. 2018 Jan 1;197(1):79-93. doi: 10.1164/rccm.201701-0134OC. PMID: 28853905. PMCID: PMC5765386.
  8. Stonebraker JR, Ooi CY, Pace RG, Corvol H, Knowles MR, Durie PR, Ling, SC. Features of severe liver disease with portal hypertension in patients with cystic fibrosis. Clin Gastroenterol Hepatol. 2016 Aug;14(8):1207-15.e3. doi: 10.1016/j.cgh.2016.03.041. PMID: 27062904. PMCID: PMC4955685.
  9. Dang H, Gallins PJ, Pace RG, Guo X, Stonebraker JR, Corvol H, Cutting GR, Drumm ML, Strug LJ, Knowles MR, O’Neal WK. Novel variation at chr11p13 associated with cystic fibrosis lung disease severity. Hum Genome Var. 2016 Jul 7;3:16020. doi: 10.1038/hgv.2016.20. eCollection 2016. PMID: 27408752; PMCID: PMC4955685.
  10. Corvol H, Blackman SM, Boëlle PY, Gallins PJ, Pace RG, Stonebraker JR, Accurso FJ, Clement A, Collaco JM, Dang H, Dang AT, Franca A, Gong J, Guillot L, Keenan K, Li W, Lin F, Patrone MV, Raraigh KS, Sun L, Zhou YH, O’Neal WK, Sontag MK, Levy H, Durie PR, Rommens JM, Drumm ML, Wright FA, Strug LJ, Cutting GR, Knowles MR. Genome-wide association meta-analysis identifies five modifier loci of lung disease severity in cystic fibrosis. Nat Commun. 2015 Sep 29;6:8382. doi: 10.1038/ncomms9382. PMID: 26417704. PMCID: PMC4589222.
  11. O’Neal WK, Gallins P, Pace RG, Dang H, Wolf WE, Jones LC, Guo X, Zhou YH, Madar V, Huang J, Liang L, Moffatt MF, Cutting GR, Drumm ML, Rommens JM, Strug LJ, Sun W, Stonebraker JR, Wright FA, Knowles MR. Gene expression in transformed lymphocytes reveals variation in endomembrane and HLA pathways modifying cystic fibrosis pulmonary phenotypes. Am J Hum Genet. 2015 Feb 5;96(2):318-28. doi: 10.1016/j.ajhg.2014.12.022. PMID: 25640674; PMCID: PMC4320265.
  12. Guo X, Pace RG, Stonebraker JR, O’Neal WK, Knowles MR. Meconium ileus in cystic fibrosis is not linked to central repetitive region length variation in MUC1, MUC2, and MUC5AC. J Cyst Fibros. 2014 Dec;13(6):613-6. doi: 10.1016/j.jcf.2014.05.005. PMID: 24920497; PMCID: PMC4253052.
  13. Guo X, Zheng S, Dang H, Pace RG, Stonebraker JR, Jones CD, Boellmann F, Yuan G, Haridass P, Fedrigo O, Corcoran DL, Seibold MA, Ranade SS, Knowles MR, O’Neal WK, Voynow JA. Genome reference and sequence variation in the large repetitive central exon of human MUC5AC. Am J Respir Cell Mol Biol. 2014 Jan;50(1):223-32. doi: 10.1165/rcmb.2013-0235OC. PMID: 24010879; PMCID: PMC3930937.
  14. Blackman SM, Commander CW, Watson C, Arcara KM, Strug LJ, Stonebraker JR, Wright FA, Rommens JM, Sun L, Pace RG, Norris SA, Durie PR, Drumm ML, Knowles MR, Cutting GR. Genetic modifiers of cystic fibrosis-related diabetes. Diabetes. 2013 Oct;62(10):3627-35. doi: 10.2337/db13-0510. PMID: 23670970; PMCID: PMC3781476.
  15. Sun L, Rommens JM, Corvol H, Li W, Li X, Chiang TA, Lin F, Dorfman R, Busson PF, Parekh RV, Zelenika D, Blackman SM, Corey M, Doshi VK, Henderson L, Naughton KM, O’Neal WK, Pace RG, Stonebraker JR, Wood SD, Wright FA, Zielenski J, Clement A, Drumm ML, Boëlle PY, Cutting GR, Knowles MR, Durie PR, Strug LJ. Multiple apical plasma membrane constituents are associated with susceptibility to meconium ileus in individuals with cystic fibrosis. Nat Genet. 2012 May;44(5):562-9. doi: 10.1038/ng.2221. PMID: 22466613; PMCID: PMC3371103.
  16. Guo X, Pace RG, Stonebraker JR, Commander CW, Dang AT, Drumm ML, Harris A, Zou F, Swallow DM, Wright FA, O’Neal WK, Knowles MR. Mucin variable number tandem repeat polymorphisms and severity of cystic fibrosis lung disease: significant association with MUC5AC. PLoS One. 2011;6(10):e25452. doi: 10.1371/journal.pone.0025452. PMID: 21998660; PMCID: PMC3188583.
  17. Taylor C, Commander CW, Collaco JM, Strug LJ, Li W, Wright FA, Webel AD, Pace RG, Stonebraker JR, Naughton K, Dorfman R, Sandford A, Blackman SM, Berthiaume Y, Paré P, Drumm ML, Zielenski J, Durie P, Cutting GR, Knowles MR, Corey M. A novel lung disease phenotype adjusted for mortality attrition for cystic fibrosis genetic modifier studies. Pediatr Pulmonol. 2011 Sep;46(9):857-69. doi: 10.1002/ppul.21456. PMID: 21462361; PMCID: PMC3130075.
  18. Wright FA, Strug LJ, Doshi VK, Commander CW, Blackman SM, Sun L, Berthiaume Y, Cutler D, Cojocaru A, Collaco JM, Corey M, Dorfman R, Goddard K, Green D, Kent JW Jr, Lange EM, Lee S, Li W, Luo J, Mayhew GM, Naughton KM, Pace RG, Paré P, Rommens JM, Sandford A, Stonebraker JR, Sun W, Taylor C, Vanscoy LL, Zou F, Blangero J, Zielenski J, O’Neal WK, Drumm ML, Durie PR, Knowles MR, Cutting GR. Genome-wide association and linkage identify modifier loci of lung disease severity in cystic fibrosis at 11p13 and 20q13.2. Nat Genet. 2011 Jun;43(6):539-46. doi: 10.1038/ng.838. PMID: 21602797; PMCID: PMC3296486.
  19. Bartlett (Stonebraker) JR, Friedman KJ, Ling SC, Pace RG, Bell SC, Bourke B, Castaldo G, Castellani C, Cipolli M, Colombo C, Colombo JL, Debray D, Fernandez A, Lacaille F, Macek M Jr, Rowland M, Salvatore F, Taylor CJ, Wainwright C, Wilschanski M, Zemková D, Hannah WB, Phillips MJ, Corey M, Zielenski J, Dorfman R, Wang Y, Zou F, Silverman LM, Drumm ML, Wright FA, Lange EM, Durie PR, Knowles MR; Gene Modifier Study Group. Genetic modifiers of liver disease in cystic fibrosis. JAMA. 2009 Sep 9;302(10):1076-83. doi: 10.1001/jama.2009.1295. PMID: 19738092; PMCID: PMC3711243.
  20. Hirsh AJ, Stonebraker JR, van Heusden CA, Lazarowski ER, Boucher RC, Picher M. Adenosine deaminase 1 and concentrative nucleoside transporters 2 and 3 regulate adenosine on the apical surface of human airway epithelia: implications for inflammatory lung diseases. Biochemistry. 2007 Sep 11;46(36):10373-83. PMID: 17696452.
  21. Morin-Kensicki EM, Boone BN, Howell M, Stonebraker JR, Teed J, Alb JG, Magnuson TR, O’Neal W, Milgram SL. Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted disruption of Yap65. Mol Cell Biol. 2006 Jan;26(1):77-87. PMID: 16354681; PMCID: PMC1317614.
  22. Neuringer IP, Sloan J, Budd S, Chalermskulrat W, Park RC, Stonebraker JR, O’Neal WK, Aris RM, Randell SH. Calcineurin inhibitor effects on growth and phenotype of human airway epithelial cells in vitro. Am J Transplant. 2005 Nov;5(11):2660-70. PMID: 16212625.
  23. Stonebraker JR, Wagner D, Lefensty RW, Burns K, Gendler SJ, Bergelson JM, Boucher RC, O’Neal WK, Pickles RJ. Glycocalyx restricts adenoviral vector access to apical receptors expressed on respiratory epithelium in vitro and in vivo: role for tethered mucins as barriers to lumenal infection. J Virol. 2004 Dec;78(24):13755-68. PMID: 15564484; PMCID: PMC533903.
  24. Holda (Stonebraker) JR, Klishin A, Sedova M, Hüser J, Blatter LA. Capacitative Calcium Entry. News Physiol Sci. 1998 Aug;13:157-163. PMID: 11390782.
  25. Hüser J, Holda (Stonebraker) JR, Kockskamper J, Blatter LA. Focal agonist stimulation results in spatially restricted Ca2+ release and capacitative Ca2+ entry in bovine vascular endothelial cells. J Physiol. 1999 Jan 1;514 ( Pt 1):101-9. PMID: 9831719; PMCID: PMC2269050.
  26. Holda (Stonebraker) JR, Blatter LA. Capacitative calcium entry is inhibited in vascular endothelial cells by disruption of cytoskeletal microfilaments. FEBS Lett. 1997 Feb 17;403(2):191-6. PMID: 9042964.
  27. Byron KL, Puglisi JL, Holda (Stonebraker) JR, Eble D, Samarel AM. Myosin heavy chain turnover in cultured neonatal rat heart cells: effects of [Ca2+]i and contractile activity. Am J Physiol. 1996 Nov;271(5 Pt 1):C01447-56. PMID: 8944626.
  28. Holda (Stonebraker) JR, Oberti C, Perez-Reyes E, Blatter LA. Characterization of an oxytocin-induced rise in [Ca2+]i in single human myometrium smooth muscle cells. Cell Calcium. 1996 Jul;20(1):43-51. PMID: 8864570.
  29. Gasser KW, Holda (Stonebraker) JR. The effect of phospholipase A2 on chloride transport by pancreatic secretory granules. Biochim Biophys Acta. 1994 Aug 24;1194(1):123-30. PMID: 8075126.
  30. Gasser KW, Holda (Stonebraker) JR. ATP-sensitive potassium transport by pancreatic secretory granule membrane. Am J Physiol. 1993 Jan;264(1 Pt 1):G137-42. PMID: 8430796.
Jaclyn Stonebraker