Profile

The principal focus of the laboratory is to define the mechansims, both stimulatory and inhibitory, that control the regeneration of liver. The regenerating liver is used as a model in which to study the cellular and molecular mechanisms of growth control in a normal, non-neoplastic tissue. The critical issues to be understood in the process are: which signals sense the acute loss of liver mass and initiate regenerative growth; which signals maintain the differentiated functions of the liver during proliferation, and which signals stop liver growth when it has reached its appropriate mass? We aim to identify the major signals that regulate regeneration, the cells and tissues in which they are generated, and the nature of the cellular and molecular cross-talk that controls them. We study these problems in whole animals, some genetically modified to overexpress or block critical regulatory molecules, and others treated with growth factors or neutralizing antibodies; in primary cultures and lines of hepatocytes and other liver-derived cells; and in subcellular fractions of cells.


A major focus in the lab is the role of EGF-like molecules in liver growth and metabolism.


Although a potent hepatic mitogen, EGF was reported long ago to have actions that both mimic and antagonize those of insulin in the liver. The EGF receptor (EGFr) is one of a family of four related tyrosine kinase receptors: EGFr, ErbB2, ErbB3, and ErbB4. Ligands of these receptors induce hetero- and homodimers and divergent downstream signaling. Adult liver expresses only EGFr and ErbB3, while fetal liver expresses EGFr, ErbB2 and ErbB3. Ligands of both the EGFr (TGFalpha, amphiregulin, epiregulin, betacellulin, and HB-EGF) and ErbB3 (heregulins or neuregulins) are expressed in liver or pancreas. The laboratory is actively investigating the proliferative and metabolic signals generated by this important system.


ErbB2, which can dimerize with either EGFr or ErbB3 is strongly expressed in fetal and neonatal liver, but is extinguished around the time of weaning, suggesting it to be a developmental switch. The model under investigation is that the ErbB receptor family transduces growth and metabolic signals in the liver, and perhaps in other tissues, and that the various ligands and receptors in this family have different actions at different developmental stages. In addition to developmental differences in ErbB receptor expression, there are also striking zonal and circadian differences in their expression, adding to the potential richness and subtlety of ErbB signaling in the liver.


Other areas of active investigation in the laboratory include the role of receptor guanylyl cyclases, the plasminogen activator system, and also of growth inhibitors in the development and regeneration of liver.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Loss of hepatocyte ERBB3 but not EGFR impairs hepatocarcinogenesis. Scheving LA, Zhang X, Stevenson MC, Weintraub MA, Abbasi A, Clarke AM, Threadgill DW, Russell WE (2015) Am J Physiol Gastrointest Liver Physiol 309(12): G942-54
    › Primary publication · 26492920 (PubMed) · PMC4683301 (PubMed Central)
  2. A review of adolescent adherence in type 1 diabetes and the untapped potential of diabetes providers to improve outcomes. Datye KA, Moore DJ, Russell WE, Jaser SS (2015) Curr Diab Rep 15(8): 51
    › Primary publication · 26084580 (PubMed) · PMC4692366 (PubMed Central)
  3. Loss of hepatocyte EGFR has no effect alone but exacerbates carbon tetrachloride-induced liver injury and impairs regeneration in hepatocyte Met-deficient mice. Scheving LA, Zhang X, Stevenson MC, Threadgill DW, Russell WE (2015) Am J Physiol Gastrointest Liver Physiol 308(5): G364-77
    › Primary publication · 25414100 (PubMed) · PMC4346751 (PubMed Central)
  4. TSH elevations as the first laboratory evidence for pseudohypoparathyroidism type Ib (PHP-Ib). Molinaro A, Tiosano D, Takatani R, Chrysis D, Russell W, Koscielniak N, Kottler ML, Agretti P, De Marco G, Ahtiainen P, Christov M, Mäkitie O, Tonacchera M, Jüppner H (2015) J Bone Miner Res 30(5): 906-12
    › Primary publication · 25403028 (PubMed) · PMC4401615 (PubMed Central)
  5. Development and validation of the diabetes adolescent problem solving questionnaire. Mulvaney SA, Jaser SS, Rothman RL, Russell WE, Pittel EJ, Lybarger C, Wallston KA (2014) Patient Educ Couns 97(1): 96-100
    › Primary publication · 25063715 (PubMed) · PMC4162751 (PubMed Central)
  6. Targeting of memory T cells with alefacept in new-onset type 1 diabetes (T1DAL study): 12 month results of a randomised, double-blind, placebo-controlled phase 2 trial. Rigby MR, DiMeglio LA, Rendell MS, Felner EI, Dostou JM, Gitelman SE, Patel CM, Griffin KJ, Tsalikian E, Gottlieb PA, Greenbaum CJ, Sherry NA, Moore WV, Monzavi R, Willi SM, Raskin P, Moran A, Russell WE, Pinckney A, Keyes-Elstein L, Howell M, Aggarwal S, Lim N, Phippard D, Nepom GT, McNamara J, Ehlers MR, T1DAL Study Team (2013) Lancet Diabetes Endocrinol 1(4): 284-94
    › Primary publication · 24622414 (PubMed) · PMC3957186 (PubMed Central)
  7. Epidermal growth factor receptor plays a role in the regulation of liver and plasma lipid levels in adult male mice. Scheving LA, Zhang X, Garcia OA, Wang RF, Stevenson MC, Threadgill DW, Russell WE (2014) Am J Physiol Gastrointest Liver Physiol 306(5): G370-81
    › Primary publication · 24407590 (PubMed) · PMC3949019 (PubMed Central)
  8. Costimulation modulation with abatacept in patients with recent-onset type 1 diabetes: follow-up 1 year after cessation of treatment. Orban T, Bundy B, Becker DJ, Dimeglio LA, Gitelman SE, Goland R, Gottlieb PA, Greenbaum CJ, Marks JB, Monzavi R, Moran A, Peakman M, Raskin P, Russell WE, Schatz D, Wherrett DK, Wilson DM, Krischer JP, Skyler JS, Type 1 Diabetes TrialNet Abatacept Study Group (2014) Diabetes Care 37(4): 1069-75
    › Primary publication · 24296850 (PubMed) · PMC3964491 (PubMed Central)
  9. Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Orban T, Bundy B, Becker DJ, DiMeglio LA, Gitelman SE, Goland R, Gottlieb PA, Greenbaum CJ, Marks JB, Monzavi R, Moran A, Raskin P, Rodriguez H, Russell WE, Schatz D, Wherrett D, Wilson DM, Krischer JP, Skyler JS, Type 1 Diabetes TrialNet Abatacept Study Group (2011) Lancet 378(9789): 412-9
    › Primary publication · 21719096 (PubMed) · PMC3462593 (PubMed Central)
  10. Pediatric endocrinologists' management of children with type 2 diabetes. Wong K, Potter A, Mulvaney S, Russell WE, Schlundt DG, Rothman RL (2010) Diabetes Care 33(3): 512-4
    › Primary publication · 20007947 (PubMed) · PMC2827499 (PubMed Central)
  11. Mitochondrial reactive oxygen species mediate GPCR-induced TACE/ADAM17-dependent transforming growth factor-alpha shedding. Myers TJ, Brennaman LH, Stevenson M, Higashiyama S, Russell WE, Lee DC, Sunnarborg SW (2009) Mol Biol Cell 20(24): 5236-49
    › Primary publication · 19846666 (PubMed) · PMC2793298 (PubMed Central)
  12. Clinical, genetic, and enzymatic characterization of P450 oxidoreductase deficiency in four patients. Sahakitrungruang T, Huang N, Tee MK, Agrawal V, Russell WE, Crock P, Murphy N, Migeon CJ, Miller WL (2009) J Clin Endocrinol Metab 94(12): 4992-5000
    › Primary publication · 19837910 (PubMed) · PMC2795645 (PubMed Central)
  13. Self-management in type 2 diabetes: the adolescent perspective. Mulvaney SA, Mudasiru E, Schlundt DG, Baughman CL, Fleming M, VanderWoude A, Russell WE, Elasy TA, Rothman R (2008) Diabetes Educ 34(4): 674-82
    › Primary publication · 18669809 (PubMed) · PMC2757076 (PubMed Central)
  14. Cultured rat hepatocytes upregulate Akt and ERK in an ErbB-2-dependent manner. Scheving LA, Stevenson MC, Zhang X, Russell WE (2008) Am J Physiol Gastrointest Liver Physiol 295(2): G322-31
    › Primary publication · 18535289 (PubMed) · PMC2519852 (PubMed Central)
  15. Evidence of metabolic syndrome in lean children with premature pubarche at diagnosis. Mathew RP, Byrne DW, Linton MF, Vaughan DE, Fazio S, Russell WE (2008) Metabolism 57(6): 733-40
    › Primary publication · 18502254 (PubMed)
  16. Self-management behaviors, racial disparities, and glycemic control among adolescents with type 2 diabetes. Rothman RL, Mulvaney S, Elasy TA, VanderWoude A, Gebretsadik T, Shintani A, Potter A, Russell WE, Schlundt D (2008) Pediatrics 121(4): e912-9
    › Primary publication · 18381520 (PubMed)
  17. It's about time: clock genes unveiled in the gut. Scheving LA, Russell WE (2007) Gastroenterology 133(4): 1373-6
    › Primary publication · 17919508 (PubMed)
  18. Dexamethasone modulates ErbB tyrosine kinase expression and signaling through multiple and redundant mechanisms in cultured rat hepatocytes. Scheving LA, Buchanan R, Krause MA, Zhang X, Stevenson MC, Russell WE (2007) Am J Physiol Gastrointest Liver Physiol 293(3): G552-9
    › Primary publication · 17585012 (PubMed)
  19. Insulin glargine supplementation during early management phase of diabetic ketoacidosis in children. Shankar V, Haque A, Churchwell KB, Russell W (2007) Intensive Care Med 33(7): 1173-1178
    › Primary publication · 17508198 (PubMed)
  20. Beta-catenin in the liver: an integrator of proliferation and metabolism? Scheving LA, Russell WE (2006) Gastroenterology 131(5): 1641-3
    › Primary publication · 17101334 (PubMed) · PMC2562022 (PubMed Central)
  21. The emergence of ErbB2 expression in cultured rat hepatocytes correlates with enhanced and diversified EGF-mediated signaling. Scheving LA, Zhang L, Stevenson MC, Kwak ES, Russell WE (2006) Am J Physiol Gastrointest Liver Physiol 291(1): G16-25
    › Primary publication · 16769812 (PubMed)
  22. Parent perceptions of caring for adolescents with type 2 diabetes. Mulvaney SA, Schlundt DG, Mudasiru E, Fleming M, Vander Woude AM, Russell WE, Elasy TA, Rothman R (2006) Diabetes Care 29(5): 993-7
    › Primary publication · 16644626 (PubMed)
  23. Sonographic findings in infants with congenital adrenal hyperplasia. Hernanz-Schulman M, Brock JW, Russell W (2002) Pediatr Radiol 32(2): 130-7
    › Primary publication · 11819084 (PubMed)