Biomedical Base
Harvard Clinical Nutrition Research Center
Biomedical Base
Cellular Biology and Nutrient-Gene Interaction
Following are the primary investigators of this theme and a brief discussion of their work.
Wayne Lencer
Dr. Lencer continues as an Investigator in the HCNRC renewal. The Lencer laboratory studies the cell and molecular biology of vesicular transport in polarized epithelial cells and regulation of ion transport in the intestine. These studies relate to how intestinal epithelial cells interact with the luminal and sub-epithelial micro-environment, and to the biology of bacterial pathogenesis and host defense at mucosal surfaces. The lab has discovered how some enteric bacterial toxins breech the intestinal epithelial barrier and enter host epithelial cells to cause disease. These toxins hijack the cellular and molecular mechanisms of retrograde membrane transport to move from the luminal cell surface into the endoplasmic reticulum (ER) of affected cells, the total reverse of protein biosynthesis. In another project, the lab studies the cell and molecular biology of the MHC Class I-like IgG receptor FcRn. FcRn transports IgG across mucosal surfaces where it may function in immune surveillance and host defense. In a third area of interest, the lab aims to understand the mechanisms and regulation of intestinal Cl- secretion, the initial ion transport event in secretory diarrhea. He is also conducting research projects on oral and pulmonary delivery of protein therapeutics and on clotrimazole for the treatment of inflammatory bowel disease.
Ian Sanderson
Dr. Sanderson continues in the HCNRC renewal as an Investigator. He has previously been a research faculty member in the Mucosal Immunology Laboratory at MGH-East for eight years before accepting a Professorship in Pediatric Gastroenterology at the University of London (St. Bartholomew’s Hospital). He retains a secondary appointment at Harvard and currently is on sabbatical in the Mucosal Immunology Laboratory. His major research interests are nutrient- gene interaction. His original clinical studies with Professor John Walker-Smith demonstrated that an elemental diet could be used to treat children with Crohn disease. He has subsequently determined the molecular mechanisms by which an elemental diet downregulates intestinal inflammation.
Biographical sketch forthcoming.
Marianne Wessling-Resnick
Dr. Wessling-Resnick continues as an Investigator in the HCNRC renewal. She and Dr. Hotamisiligil are part of a new department at the HSPH, the Department of Genetics and Complex Diseases. She has also trained two P/F awardees over the last ten years. Current research efforts in the Wessling-Resnick lab focus on: 1) Ferroportin-1 function and regulation: Macrophages of the reticuloendothelial system play a major role in iron metabolism by recycling iron from red blood cells. Dr. Wessling-Resnick’s studies have documented a role for the iron exporter FPN1 in this process. Mutations in FPN1 have been described to promote an iron overload disorder called “ferroportin disease” and current investigations are studying how the known human mutations affect FPN1 function; and 2) Discovery of Small Molecule Inhibitors of Iron Uptake: One focus on the cellular uptake of iron by the Wessling-Resnick laboratory has been to develop pharmacological tools to help advance our molecular understanding of the pathways involved. Dr. Wessling-Resnick has established a cell-based screen that enables the rapid identification of iron transport inhibitors and have discovered ten novel small molecule inhibitors of non-transferrin bound iron uptake. Ongoing studies focus on characterizing their mechanisms of inhibition.
Joel Habener
Dr. Habener continues as an Investigator with the HCNRC renewal application. He is an internationally recognized molecular endocrinologist with strong interests in glucagon metabolism and hormonal regulation of glycoprotein metabolism. As a Howard Hughes Investigator, he studies the gene regulation of polypeptide hormones including somatostatin and glycoprotein hormone. His studies of insulin metabolism and leptin interaction and intracellular signaling in adipocyte function have helped elucidate the relationship with obesity and type II diabetes. His more recent research interests includes: (1)The regulation of the development of and gene expression in the endocrine pancreas involving pancreatic stem/progenitor cells. (2) The cellular processes involved in the coupling of extracellular stimuli to the synthesis and release of hormones—studies are being conducted in both in vivo and in vitro systems. (3) The pathogenesis of dysfunction of the b-cell in type 2 diabetes involving glucotoxic impairment of intracellular signal transduction pathways.
Nancy Andrews
Dr. Andrews joins the HCNRC renewal as a new Investigator. In addition to her strong basic science background in iron metabolism, she is also the newly appointed Dean of Basic Sciences and Graduate Studies at HMS. Dr. Andrews’ research interests focus on molecular hematology, mammalian iron homeostasis and mouse models of human diseases. Her laboratory has identified novel proteins involved in iron metabolism through positional cloning of spontaneous mouse and rat mutations that result in iron deficiency anemia. They have also used gene targeting to disrupt iron-related genes in mice, to make mouse models of iron overload disorders and to study iron balance. Recently, they described a role for a new iron-regulating hormone in the pathogenesis of the hemochromatosis and the anemia of inflammation in human patients.
Joseph Avruch
Dr. Avruch continues as an Investigator in the HCNRC renewal. His research program is aimed at identifying the molecular structure, function and regulation of the elements that mediate signal transduction initiated by the insulin receptor, related receptor tyrosine kinases and counter-acting, anti-insulin signaling pathways. As elucidation of the signaling pathways responsive to insulin progressed, it became evident that many of the effectors identified also participated in the implementation of mitogenic and cell differentiation programs. Thus the mechanisms uncovered in this effort proved to have important implications not only for metabolic regulation and its disorders i.e., diabetes and obesity, but also for states characterized by disordered cell growth regulation. These efforts were undertaken in collaboration with Drs. Nathan, Gulick, and Faustman. Dr. Avruch has recently relocated his laboratory to the Department of Molecular Biology at MGH. He now works closely there with Drs. Ausubel. These studies have and will continue to make extensive use of the Molecular Biology/Genomics Core for experiments involving protein/gene interaction, for oligonucleotides and for planned genomic studies. He also uses the Cell Biology Core for identification of signal transduction molecules and for transfection experiments. In addition, Dr. Avruch acts as a resource for investigators in the Center doing signal transduction experiments.
Tod Gulick
Dr. Gulick joins the HCNRC renewal as a new Investigator having been in previous granting periods an Associate Investigator and P/F awardee. As a result of two years of P/F funding in the first funding period (1994-1999) he has been successful in obtaining extensive NIH grant support and now has an independent laboratory. His primary interest is in the cellular metabolism of lipids and the role of antiviral therapy in AIDS. With a P/F award in the initial grant application, he characterized a carnithine/acylcarnthine transporter to better understand the toxicities associated with antiretroviral therapy with AIDS. This work has resulted in a funded RO1. More recently he has studies transcriptional control of genes that encode key enzymes involved in fuel oxidation in muscle to better understand aspects of the metabolic syndrome. These studies have also resulted in a funded RO1. Finally, he is currently studying the role of nutrients in cellular/organ development at the molecular level. He collaborates extensively with Drs. Avruch, Faustman, Grinspoon, Leaf, Neufeld, Newburger, and plans future collaborations with Drs. Spiegelman, Hotamisiligil, and Habener. He also uses the Genomics and Cell Biology Cores extensively.
Bruce Spiegelman
Dr. Bruce Spiegelman joins the HCNRC renewal as a new Investigator. He is an internationally recognized cell biologist investigating fat metabolism in the adipocyte and hepatocyte. He received the Bristol Myers Squibb Excellence in Metabolic Research Award in 2003 and became a member of the National Academy of Science in 2002. His research environment has spawned HCNRC Investigators such as Gokhan Hotamisiligil, M.D., Ph.D. (Chairman of the Genetics and Complex Disease Department at HSPH and an Investigator in the HCRNC) and Pi Ling Kim, Ph.D. a possible new faculty member of the Nutrition Department at HSPH and a possible Associate Investigator and P/F applicant in the HCNRC depending on his final decision for a faculty appointment. His research interests include the role of nuclear receptors (PPARg) in energy metabolism and the cellular mechanism of trans- and saturated fatty acid metabolism in hepatocytes through transcription co-activators. His laboratory has begun to explain the cellular mechanisms of LDL cholesterol elevation after exposure to trans fatty acids and provides a molecular mechanism explanation of how diets affects dyslipidemias in cardiovascular disease.
Joseph Majzoub
Dr. Majzoub joins the HCNRC renewal as a new Investigator. Dr. Majzoub has a strong interest in molecular endocrinology, particularly the role of stress on organ development in the newborn. Most recently he has become interested in the neuroendocrine mediation of satiety particularly as it pertains to the glycemic index. As the former PI of the GCRC at Children’s Hospital, he has become interested in clinical aspects of pediatric obesity.