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.

Biography

Following medical school, I pursued clinical training in pediatrics. It was during my residency that I became interested in biomedical research. This led to a metabolism fellowship, clinical training in metabolism and pediatric endocrinology, and a research focus on mechanisms that regulate somatic growth. My laboratory has had continuous NIH funding since 1983, and I have been a trainer in Brown's MCB and Pathobiology training programs since 1995.

Institutions

Rih

Research Description

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 system is 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 a rather 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 control and cell cycle control mechanisms that appear to relate to the dysregulated growth seen in the liver's response to carcinogens and injury.

Awards

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

Affiliations

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-present

HOSPITAL APPOINTMENTS

Staff Physician, Rhode Island Hospital, July 1994-present

Funded Research

1. Special Emphasis Research Career Award, "Diabetes Mellitus: Pediatric Aspects", from NIDDK, Total direct costs: $263,850, 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, Total direct costs: $268,033, 1985 - 1988
3. Basil O'Connor Starter Research Grant from the March of Dimes Birth Defects Foundation, Total direct costs: $70,546, 1986 - 1989
4. Principal Investigator, Juvenile Diabetes Foundation International Research Grant, "Protein Tyrosine Phosphatases in Diabetes", Total direct costs: $87,882, 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", Total direct costs: $285,525, 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, Total direct costs: $573,283, 1991 - 1996
8. Principal Investigator, NIH Basic Research Grant, RO1 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", Total Direct Costs: $369,705, 1991 - 1994
10. Consultant, NIH Grant "Improving Children's Health Outcome: Negotiating Care"; Principal Investigator, S. Kaplan, 1992 - 1993
11. Renewal of HD24455, Total direct costs: $348,337, 1993 - 1997
12. Principal Investigator, Subproject #1, "Regulation of Fetal Hepatic Development," Program Project Grant ("The Biological Basis for Perinatal Transition"), HD11343, Total direct costs: $502,725, 1996 - 2001
13. Renewal of R01 HD24455, Total direct costs: $536,992, 1997 - 2001
14. Eli Lilly Fellowship Support Grant, Total costs: $10,000, 1997 - 1998
15. Fellowship Research Training Grant, Novo Nordisk Pharmaceuticals, Inc., Total costs: $7,000, 1998 - 1999
16. Principal Investigator, NIH Basic Research Grant, R01 HD35831: "Insulin Resistance in the Growth Retarded Fetal Rat." Total direct costs: $384,708, 1999 - 2003
17. Eli Lilly Fellowship Support Grant, Total costs: $20,000, 1999 - 2000
18. Trainer for Perinatal Training Grant (T32 HD007511; PI: James Padbury): "Perinatal Biology Training Grant." 1999 – 2004
19. Eli Lilly Fellowship Support Grant, Total costs: $20,000, 2000 - 2001
20. Renewal of R01 HD24455, Total direct costs: $1,125,000, 2001 - 2006
21. Eli Lilly Fellowship Support Grant, Total costs: $20,000, 2001 - 2002
22. Principal Investigator, NIH Basic Research Grant, R01 DK/HD59815: "Hepatocyte Proliferation during Development, Role of p38" (Replaces HD11343). Total direct costs: $725,000, 2002 - 2007
23. Eli Lilly Fellowship Support Grant, Total costs: $10,000, 2002 - 2003
24. Sponsor: National Research Service Award (HD041893) to Rosa Jimenez (MD/PhD candidate), 2001 – 2006
25. Collaborator (PI, Charlotte Boney), NIH Basic Research Grant, R01 DK59339: "The Role of Src Kinases in IGF-I-Mediated Adipogenesis." 12/1/01 - 11/30/06
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." 6/1/03 - 5/31/04
28. Mentor and Scientific Advisor, COBRE Grant (P20RR017695; PI: Douglas Hixson): "Center for Cancer Research Development." 2002 - 2007
29. Eli Lilly Fellowship Support Grant, Total costs: $10,000, 2003 - 2004
30. Trainer for Liver Center Training Grant (T32 DK060415; PI: Jack Wands): "Research Training Program in Gastroenterology." 2003 - 2008
31. Renewal of R01 HD35831: Title changed to "Nutritional Regulation of Fetal Liver Development." Total direct costs: $787,500, 2003 - 2008
32. Eli Lilly Fellowship Support Grant, Total costs: $10,000, 2004 - 2005
33. Sanofi-Aventis Educational Grant – Continuing Education in the Management of Type 1 Diabetes in Childhood, Total costs: $3,000, 2005
34. Renewal of R01 HD24455, Total direct costs: $1,105,000, 2007 – 2012
35. Mentor and Co-Investigator, 1P20RR024484, COBRE for Skeletal Health and Repair, (PI, Dr. Q. Chen); 2007 - 2012
36. Faculty Trainer, 1R25GM083270, Advancing the Culture of PhD Learning and Scholarship in Biology and Health Science (PIs, Drs. A Campbell and N. Thompson); 2008 - 2012
37. Mentor and Project Co-Investigator, 2P20RR017695, COBRE Center for Cancer Research Development (PI, Dr. D. Hixson); 2009 – 2014
38. PI and Program Director, 1T35HL094308, Alpert Medical School Summer Research Program (NIH/NHLBI support for medical student basic research); 2009 – 2014

Teaching Experience

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. My present role includes course director responsibility for the first year medical course entitled Integrated Medical Sciences - Scientific Foundations of Medicine.

Courses Taught

• Integrated Medical Sciences I (BI0364)
• Integrated Medical Sciences II (BI0365)

View My Full Publication List in pdf format

Selected Publications

• Jimenez RH, Boylan JM, Lee J-S, Francesconi M, Castellani G, Sanders JA, Gruppuso PA: Rapamycin response in tumorigenic and non-tumorigenic hepatic cell lines. PLoS ONE (in press)(IN PRESS)
• Phornphutkul C, Lee M, Voigt C, Wu K-Y, Ehrlich MG, Gruppuso PA, Chen Q: The effect of rapamycin on bone growth in rabbits. J Orthopedic Research 27:1157-1161, 2009.(2009)
• Kim MS, Wu K-Y, Auyeung V, Chen Q, Gruppuso PA, Phornphutkul C. Leucine restriction inhibits chondrocyte proliferation and differentiation through mechanisms both dependent and independent of mTOR signaling. Am J Physiol 296:1374-1382, 2009. [PMCID: PMC2692404](2009)
• Yoo J-S, Jimenez RH, Sanders JA, Boylan JM, Brautigan DL, Gruppuso PA: The alpha4-Containing Form of Protein Phosphatase 2A in Liver and Hepatic Cells. J Cell Biochem 105:290-300, 2008. [PMCID: PMC2597445](2008)
• Sanders JA, Lakhani A, Phornphutkul C, Wu K-Y, Gruppuso PA: The Effect of Rapamycin on DNA Synthesis in Multiple Tissues from Late Gestation Fetal Rats and Postnatal Rats. Am J Physiol Cell Physiol 295:C406-C413, 2008. [PMCID: PMC2518428](2008)
• Gruppuso PA, Tsai S-W, Boylan JM, Sanders JA: Hepatic translation control in the late gestation fetal rat. Am J Physiol Regul Integr Comp Physiol 295:R558-R567, 2008. [PMCID: PMC2519922](2008)