Our laboratory focuses on the regulation of normal and abnormal cellular growth. We use liver as the model tissue for our studies. We rely on animal models, cell culture, and human tissue. We study control of fetal growth, tissue regeneration, and tissue injury, including injury that can lead to cancer. Our goals are to understand how nutrition and other environmental factors affect cell growth, and to develop cell-based therapeutic approaches suitable for liver diseases, including cancer.

Our laboratory is focused on the mechanisms that regulate normal and abnormal cellular growth. We use the liver as a model system to study the control of hepatocyte proliferation during normal liver development, liver regeneration and liver injury. We do so based on the premise that understanding normal hepatocyte growth regulation will provide insight into abnormal growth (cancer) and the proliferative response of the liver's facultative stem cells to liver injury. We have concentrated on the following areas: developmental stage-specific alterations in hepatocyte mitogenic signaling, changes in translation control during the perinatal period, and hepatocyte cell cycle control during development. Our model systems are the rat and mouse with a particular focus on the tripling of liver mass that takes place during the last several days of gestation. Our work employs both in vitro (primary culture and hepatic cell lines) and in vivo approaches.

We have arrived at an unexpected picture of how hepatocyte proliferation is regulated through late fetal and postnatal development. Our data indicate that the stimulation for rapid fetal hepatocyte growth is largely independent of the signal transduction pathways that stimulate the proliferation of adult rat hepatocytes. A manifestation of this difference between fetal and adult hepatocyte growth control is the resistance of fetal hepatocytes to the growth (translation and cell cycle) inhibitory effects of the drug rapamycin. Rapamycin resistance is a characteristic previously attributed to transformed cell types. In pursuing this observation, we have identified translation and cell cycle control mechanisms that appear to relate to the dysregulated growth seen in the liver's response to carcinogens and injury. Most recently, we have begun to focus on the regenerative capacity of fetal liver cells, their epigenetic phenotype, and their ability to repopulate an injured adult liver.

1. Special Emphasis Research Career Award, "Diabetes Mellitus: Pediatric Aspects," from NIDDK, 1983-1988
2. Co-Investigator, Subproject #5, "Pancreatic Endocrine Function in the Hyperinsulinemic Fetus", Perinatal Emphasis Research Center ("Diabetes During Pregnancy: Effects on the Offspring"), HD11343, 1985-1988
3. Basil O'Connor Starter Research Grant from the March of Dimes Birth Defects Foundation, 1986-1989
4. Principal Investigator, Juvenile Diabetes Foundation International Research Grant, "Protein Tyrosine Phosphatases in Diabetes," 1988-1990
5. American Diabetes Association Feasibility Grant (approved and funded, but award not accepted upon receipt of JDF grant), 1988
6. Principal Investigator, NIH Basic Research Grant, RO1 HD24455, "Regulation of Fetal Hepatic Growth," 1989-1993
7. Principal Investigator, Subproject #5, "Regulation of Fetal Hepatic Development by Insulin," Perinatal Emphasis Research Center ("Diabetes During Pregnancy: Effects on the Offspring"), HD11343, 1991-1996
8. Principal Investigator, NIH Basic Research Grant, R01 HD28324: "Mechanisms Regulating Hepatic Growth in IUGR Fetuses" (Funded with a priority score of 151 but not accepted upon funding of above PERC), 1991
9. Collaborator, NIH Basic Research Grant, RO1 CA55892 (Principal Investigator, L. Braun): "Growth Regulation in Cervical Neoplasia," 1991-1994
10. Consultant, NIH Grant "Improving Children's Health Outcome: Negotiating Care" (Principal Investigator, S. Kaplan), 1992-1993
11. Renewal of HD24455, 1993-1997
12. Principal Investigator, Subproject #1, "Regulation of Fetal Hepatic Development," Program Project Grant ("The Biological Basis for Perinatal Transition"), HD11343, 1996-2001
13. Renewal of R01 HD24455, 1997-2001
14. Eli Lilly Fellowship Support Grant, 1997-1998
15. Fellowship Research Training Grant, Novo Nordisk Pharmaceuticals, Inc., 1998-1999
16. Principal Investigator, NIH Basic Research Grant, R01 HD35831: "Insulin Resistance in the Growth Retarded Fetal Rat." 1999-2003
17. Eli Lilly Fellowship Support Grant, 1999-2000
18. Trainer, T32 HD007511 (PI: J. Padbury): "Perinatal Biology Training Grant." 1999-2004
19. Eli Lilly Fellowship Support Grant, 2000-2001
20. Renewal of R01 HD24455, 2001-2006
21. Eli Lilly Fellowship Support Grant, 2001-2002
22. Principal Investigator, NIH Basic Research Grant, R01 DK/HD59815, "Hepatocyte Proliferation during Development, Role of p38" (Replaces HD11343), 2002-2007
23. Eli Lilly Fellowship Support Grant, 2002-2003
24. Sponsor: National Research Service Award (HD041893) to Rosa Jimenez (MD/PhD candidate), 2001-2006
25. Collaborator, R01 DK59339, "The Role of Src Kinases in IGF-I-Mediated Adipogenesis" (PI, C, Boney) 2001-2006
26. Sponsor: National Research Service Award (HD041893) to Odmara Barreto-Chang (MD/PhD candidate), 2002-2007
27. Sponsor for K08 grant, PI: William Reiner (MH01777): "Gender Identity: Sex-Reassignment Due to Genital Defects," 2003-2004
28. Mentor and Scientific Advisor, COBRE Grant P20 RR017695 (PI: Douglas Hixson), "Center for Cancer Research Development," 2002-2007
29. Eli Lilly Fellowship Support Grant, 2003-2004
30. Trainer for Liver Center Training Grant T32 DK060415 (PI, J. Wands), "Research Training Program in Gastroenterology," 2003-2008
31. Renewal of R01 HD35831: Title changed to "Nutritional Regulation of Fetal Liver Development." 2003-2008
32. Eli Lilly Fellowship Support Grant, 2004-2005
33. Sanofi-Aventis Educational Grant – Continuing Education in the Management of Type 1 Diabetes in Childhood, 2005
34. Renewal of R01 HD24455, 2007-2012
35. Mentor and Co-Investigator, 1 P20 RR024484, "COBRE for Skeletal Health and Repair," (PI, Dr. Q. Chen); 2007-2012
36. Faculty Trainer, 1 R25 GM083270, "Advancing the Culture of PhD Learning and Scholarship in Biology and Health Science" (PIs, A. Campbell and N. Thompson), 2008-2012
37. Mentor and Project Co-Investigator, 2 P20 RR017695, "COBRE Center for Cancer Research Development" (PI, D. Hixson); 2009-2014
38. PI and Program Director, 1 T35 HL094308, "Alpert Medical School Summer Research Program" (NIH/NHLBI support for medical student basic research), 2009-2014
39. Project Director and Pediatric Specialist, 1 P20 ES018169, "Formative Center for the Evaluation of Environmental Impacts on Fetal Development" (PI, Dr. K. Boekelheide), 2010-2013
40. PI, "Promoting Primary Care Career Choices in Rhode Island," Rhode Island Foundation, 2011-2012
41. Co-PI (Collaborative grant with Albert Einstein College of Medicine), 1 R25 HD068835, "Strengthening Behavioral & Social Science in Medical School Education," 2011-2016
42. Renewal of R01 HD24455, "Novel Approaches to Understanding the Nutrient Regulation of Fetal Somatic Growth," 2012-2017
43. AMA, "Accelerating Change in Medical Education," 2013-2018
44. Principal Invetigator, NIH Basic Research Grant, R01 DK100301, “The Fetal Hepatocyte Phenotype and Cell-Based Therapy for Liver Disease,” 2014-2018

• Phi Beta Kappa, 1973
• Haffenreffer Fellowship Award in Pediatrics at Brown University, 1981, 1982
• Listed in Woodward/White's Best Doctors in America, 1996, 1998, 2003, 2006, 2007, 2009
• American Academy of Pediatrics, Award for Excellence in Research, 1996
• Dean's Teaching Excellence Award, Brown University, 2001, 2002, 2005, 2006,2009, 2010, 2013, 2015

ACADEMIC APPOINTMENTS

Professor of Pediatrics, Brown University, 1994-present
Professor of Molecular Biology, Cell Biology & Biochemistry (Research), Brown University, 1994-present
Associate Dean for Medical Education, August 2005-2013

Professor of Medical Science, September 2015-present

HOSPITAL APPOINTMENTS

Staff Physician, Rhode Island Hospital, July 1994-2012

Since my original faculty appointment in Brown in 1983, I have had a role in both the pre-clerkship and clinical medical curricula. My involvement in medical education, including the directorship of Brown's MD/PhD program for several years, led to my appointment as Associate Dean for Medical Education in 2005, a position I held until June 2013. My present role is as a lecturer in the medical school's preclerkship curriculum. The focus of my teaching is biochemistry, nutrition science and pharmacology.