Biomedical Base
Harvard Clinical Nutrition Research Center
Biomedical Base
Nutrition Metabolism
Following are the primary investigators of this theme and a brief discussion of their work.
Harold Jueppner
Dr. Jueppner continues as an Investigator in the HCNRC renewal. Dr. Jueppner’s research involves the regulation of calcium homeostasis in mammals. His specific interest is parathyroid hormone (PTH) and its receptor (PTHrP). High concentrations of PTHrP are found in breast milk which implies that this peptide may serve important functions, at least in the neonatal gastrointestinal intestinal tract. The molecular cloning of the cDNA and the gene encoding the PTH/PTHr receptor provided novel approaches to identify and study target tissues for PTH and PTHrP action, and to define receptor defect(s) in human diseases. Through genetic studies Dr. Jueppner has shown that PHP-lb links to an area on chromosome 2Oql3 which contains the stimulatory G protein, and it appears likely that the disorder is caused by an abnormal regulation of Gsa expression, possible caused by mutations in a tissue- and/or cell-specific enhancer or promoter. The further molecular definition of PHP-Ib will provide not only a better understanding of the pathophysiology of the disease, but may also improve the therapeutic approaches to correct, through the use of vitamin D analogs and calcium supplements, disturbances in mineral ion homeostasis. Dr. Jueppner’s background in the molecular mechanism of calcium and vitamin D metabolism adds to the nutrition metabolism group in the HCNRC.
Lynne Levitsky
Dr. Levitsky continues as an Investigator in the HCNRC renewal. Her laboratory is investigating the mechanism of glucose transport in human fetal and adult hepatocytes in order to understand the effects of the fetal and postnatal milieu upon the large changes in carbohydrate metabolism that occur in the perinatal period. They are examining the effect of the fetal metabolic milieu upon glucose transport in human fetal hepatocytes compared with human adult hepatocytes and rat hepatocytes. In addition, she has recently developed an interest in anorexia nervosa and type II diabetes.
David Rhoads
Dr. Rhoads joined the HCNRC as an Investigator during the last funding period and has continued in the renewal. He was a P/F recipient who obtained NIH funding during the previous funding period. His research is a follows: a number of intestinal transporters and enzymes for carbohydrate metabolism are both diurnally expressed and induced by dietary carbohydrate. The anticipatory nature of these behaviors, particularly of the diurnal periodicity, led him to hypothesize a genetically controlled adaptive mechanism. From these studies, he has concluded that a circadian transcriptional rhythm, conserved between rodents and primates and regulated in part by hepatocyte nuclear factor 1 (HNF1), underlies the circadian rhythm of enzyme activities observed in many tissues. He postulates that the rhythmicity in enzyme activities contributes to changes in carbohydrate tolerance and insulin sensitivity. To elucidate the transcriptional mechanism(s) regulating carbohydrate metabolism, he is characterizing the diurnal control of carbohydrate-responsive genes in normal rodents as well as in surgical and genetic knockout models. In addition, he is examining the relationship between intrauterine growth restriction (IUGR) and the development of insulin resistance (IR). In adults, accumulation of intramyocellular lipids (IMCL) precedes IR. Moreover, growth hormone (GH) treatment for short stature resulting from IUGR can exacerbate IR despite its positive effects on body composition. His overall goal is to evaluate IMCL content, measured non-invasively, as a determinant of IR in IUGR children and to assess the impact of GH therapy on this relationship.
Ronald Tompkins
Dr. Tompkins continues as an Investigator in the HCNRC renewal. He obtained a Ph.D. from M.I.T. in biomedical engineering. With this background and an interest in trauma surgery, he has established a strong research program in hepatocyte metabolism in postburn trauma. The overall specific aim of his project is to identify the cellular and molecular events that account for the catabolic state of nitrogen (amino acid) metabolism in the liver of the burned host. These studies may enhance an interpretation of the findings emerging from studies in human volunteers compared to burned patients and potentially provide a better basis for the design of future in vivo studies of burn metabolism. Regarding the drivers of this hypermetabolic response, one possible hypothesis identifies neurohormonal alterations as the cause for the increases in metabolic rate, glucose turnover, lipolysis, whole body protein turnover, negative nitrogen balance and insulin resistance. However, when the counter regulatory hormones of stress which include glucagon, hydrocortisone and epinephrine were infused in normal human volunteers, the response was only modest with respect to metabolic rate, urinary nitrogen loss and amino acid fluxes. With this approach, Dr. Tompkins may be able to “normalize” the hypermetabolic response to stress by blocking or modulating factors allowing appropriate nutritional support and medical management to reverse the dramatic wasting and significantly improving the likelihood of the patient’s survival.
Biographical sketch forthcoming.
Dr. Bistrian continues as an Investigator in the HCNRC with the renewal application. His principal clinical research interests presently are in the role of conditional essential fatty acid deficiency in some of the clinical manifestations of end stage liver disease. His basic research interests involves study of the signaling events in response to endotoxin, cytokines like interleukin 1, tumor necrosis factor, and interleukin 6 and anabolic hormones including insulin, insulin-like growth factor-1, and growth hormone using molecular biologic approaches. His laboratory also have a great interest in measurements of body composition in end stage diseases particularly renal disease and end stage liver disease. They are at present using the USDA Human Nutrition Research Unit at Tufts for research methods in body composition in collaboration with Dr. Roberts. Dr. Bistrian is the past president of the American Society for Clinical Nutrition (ASCN) and has a strong nutrition research program at BIDMC, and provides a major presence in the nutrition metabolism program.
Vivian Shih
Dr. Shih continues as an Investigator in the HCNRC renewal. Her research is centered around inherited metabolic disorders and includes studies of the molecular, biochemical, clinical, and pathological aspects of metabolic disorders of amino acids, organic acids, fatty acids and related compounds. These disorders cause mental retardation and other eurological and metabolic complications, and are often amenable to early treatment. Fumarase deficiency is a rare metabolic disorder causing severe neurological disease and often death in early childhood. Dr. Shih’s laboratory is characterizing the enzyme abnormalities and performing molecular analysis in a series of patients with different ethnic backgrounds and recently identified the first case of uniparental partial isodisomy in fumarase deficiency. Dr. Shih is interested in the management and prevention of obesity in youngsters with inborn errors of metabolism on treatment with special diets. Dr. Shih’s laboratory has also performed metabolic, therapeutic, and mutation studies in a hypohomocysteinemic syndrome due to isolated sulfite oxidase deficiency, a disorder with early onset of severe neurological defects. Another project is examining the relationship of fetal fatty acid oxidation defects (FAOD) with respect to the pathophysiology of the maternal liver disease (acute fatty liver of pregnancy and HELLP syndrome) in an attempt to characterize these disease states for improved future maternal-fetal outcomes. Studies of the long-term effects of prospective treatments for patients with inborn errors detected by routine newborn screening are ongoing. Dr. Shih, a Pediatric Neurologist with a strong research interest in amino acidopathies.
Gordon Williams
Dr. Williams continues as an Investigator in the HCNRC renewal. His research program over the past 25 years has been focused on the relationship between hormones, dietary factors and the vascular system, with a particular emphasis on genetics of blood pressure control. His primary thesis has been that the genetic determinant of hormonal responses to dietary intake are major mechanisms involved in cardiovascular disease, particularly for hypertension and renal disease associated with diabetes mellitus. His work of defining the first substantial segment of the hypertensive population who have a genetic component (non-modulators) was developed because of this interest in electrolyte intake and the response of vascular and hormonal systems to pressor agents, specifically angiotensin II. He has pursued these studies at the genetic level, defining that the polymorphism in the angiotensinogen gene is the likely genetic determinant of the non-modulating phenotype. This altered phenotype is expressed only in the presence of a high dietary sodium intake. Furthermore, insulin resistance appears to be another component. Therefore, factors involved in insulin resistance --- such as obesity --- are principal areas of focus for his current research in humans. Dr. Williams continues in the HCNRC as part of the renewal application in two capacities: (1) as an Investigator and (2) as a Director of the GCRC at the Brigham and Women’s Hospital (MO1-RR02635). He also has a funded K-30 grant (HL 04095) from NIH for Scholars in Clinical Science Program to fund M.D. clinical investigators throughout the Harvard community to learn to do clinical research.
Martin Yarmush
Dr. Yarmush continues as an Investigator in the HCNRC renewal. He studies metabolic engineering and human disease. He has a M.D./Ph.D. in biochemistry and works at the SBI. Metabolic abnormalities exist in most severe injuries and chronic diseases like cancer and AIDS. Drastic alterations in substrate turnover, including increased gluconeogenesis and urea synthesis, lead to malnutrition and loss of lean body mass. Despite the seriousness of these complications, few effective therapies have been developed because the underlying mechanisms are not well understood. His overall objective is to quantitatively account for the metabolic alterations that are produced by the inflammatory response to major injury or disease. In his studies, the flow of substrates through an organ is experimentally determined (e.g. liver or muscle) under both normal and pathologic conditions. Flux balance equations are formulated, which enable simultaneous calculations of the rates of overall substrate utilization and production and intracellular reactions. Model reaction schemes that describe the major characteristics of the metabolic reaction network are used to determine the distribution of flows of material within the model systems. These experimental and theoretical analyses of metabolic alterations produced by injury and/or disease will help identify the key differences between normal and pathologic conditions, give insight into the evolution of diseases, and suggest better nutritional therapies for patients with severe injuries and/or chronic diseases.
Biographical sketchforthcoming.
Dr. Grand joins the HCNRC renewal as a new Investigator, member of the Executive Committee and resource for clinical nutrition research in children as PI of the GCRC at CH. He has had a longstanding interest in the development of lactase expression and in the nutrition management of pediatric patients with IBD. The Grand laboratory’s basic research is devoted to two projects: the molecular regulation of intestinal lactase-phlorizin hydrolase and its enterocyte mRNA localization. Lactase is absolutely required for the survival of virtually all mammalian neonates, and its transcriptional regulation was first delineated by the Grand laboratory. Lactase expression in animals is high in infancy and declines at weaning. In humans, its expression pattern demonstrates two phenotypes. The first, expressed by the majority of the world’s population, is a decline in lactase activity at about 5-7 years of age. The second is a genetic mutation that produces persistent lactase activity in peoples of or from Northern Europe and clusters of populations elsewhere. Complex transcription factor interactions throughout the 5΄ flanking region of the lactase gene account for the decline in lactase activity in animals; and it is likely that similar mechanisms regulate the human lactase gene. His laboratory is working on the molecular basis of these phenotypes. Lactase and other proteins of the enterocyte microvillus membrane must be targeted apically during synthesis and processing, and the Grand laboratory has discovered that the mRNAs for many of these proteins are localized apically as well. In contrast, mRNAs for the cytoskeletal proteins, villin and BBMI, are located basally while their proteins are localized apically in the microvillus membrane. Messenger RNAs encoding cytosolic proteins are not localized. Using a model system in Caco-2 cells, studies are in progress to elucidate the mechanisms involved in mRNA translocation to the apical pole and the dichotomous localization patterns of mRNAs and proteins targeted to the basal region of the cells. Dr. Grand’s clinical research has focused on growth and nutrition in chronic disease, with a particular emphasis on pediatric inflammatory bowel disease. As the PI on the CH GCRC, he is in a position to oversee clinical nutrition protocols in this setting. His group was the first to recognize the nutritional basis of growth failure in IBD, and to conceptualize a therapeutic strategy for its therapy. He has recently received funding from the Crohn’s and Colitis Foundation of America for a controlled clinical trial of nasal calcitonin in the treatment of osteopenia and osteoporosis in children with inflammatory bowel disease.
Michael Holick
Dr. Holick joins the HCNRC renewal as a new Investigator and as Director of the Boston University GCRC. Dr. Holick and his team of researchers continue to be leaders in the field of vitamin D metabolism, osteoporosis, metabolic bone disease and psoriasis. His research is as follows: Plasmid gene constructs using the 25-hydroxyvitamin D-1a-hydroxylase (1-OHase) were made and successfully transfected into cultured human skin cells and several prostate cancer cell lines. The introduction of the 1-OHase gene into prostate cancer cells resulted in a marked increase in the expression of 1-OHase in the mitochondria. These cells increased their capacity to produce 1,25-dihydroxyvitamin D3, which down regulated cell growth. Research is underway to develop a new gene therapy approach for treating prostate cancer. The 1-OHase plasmid construct was topically applied to mouse skin and it was demonstrated that the gene was expressed in vivo. This offers a gene therapy approach for treating hyperproliferative skin disorders such as psoriasis and skin cancer. The expression of the 1-OHase was identified in normal human colon tissue and human colon cancer tissue. This observation provides additional evidence that the production of 1.25-dihydroxyvitamin D3 by the breast, colon and prostate may be important for regulation of cellular proliferation and cancer prevention. The receptor agonist of parathyroid hormone related peptide, PTH (1-34) was successfully formulated in a liposomal cream (Novasome A®) and a pilot clinical trial was initiated to evaluate the safety and efficacy of topical administration of PTH (1-34) for the treatment of psoriasis. The results of the pilot study suggests that PTH (1-34) is both safe and effective for treating psoriasis, and offers a novel approach for treating this skin disease. Studies were initiated on the evaluation of PTH (1-34) and PTH(7-34) for preventing and treating chemotherapy induced alopecia. C57 BL6 mice that received cyclophosphamide and that were pretreated with PTH (7-34) were able to preserve their hair to greater extent than the placebo treated mice. PTH(1-34) was effective in accelerating hair regrowth in mice that received cyclophosphamide. He brings this expertise in Vitamin D and calcium metabolism to the HCNRC