Research Activities

Vincenzo Cirulli, M.D., Ph.D.

Dr. Cirulli has focused his research on understanding the role of cell-to-cell and cell-to-matrix adhesion molecules in the development and function of pancreatic islet cells. He has identified novel adhesion and migratory cues that affect pancreatic cell development and function. Recently, Dr. Cirulli has discovered the important role of Netrin-4 as an extracellular regulator for the acquisition and maintenance of insulin and glucagon gene expression by putative pancreatic progenitor cells. Dr. Cirulli also discovered that the neural chemo-repellent Slit-2 is expressed in human pancreatic islets and has multiple complementary functions in the biology of islet cells. In a similar line of research, Dr. Cirulli is developing transgenic animal models to study the function of adhesion molecules in vivo. For these studies he is taking advantage of Tamoxifen-inducible Cre/lox-mediated DNA recombination that can direct the over-expression or ablation of select adhesion receptor in islet cells and in populations of putative islet progenitors.

Michael Gottschalk, M.D., Ph.D.

Dr. Gottschalk is involved in clinical trials related to diabetes mellitus in children, including studies on the immunomodulation of type 1 diabetes, pharmokinetic/pharmocodynamic studies of exenatide in type 2 diabetes mellitus and behavioral modification of obese adolescents at risk for type 2 diabetes mellitus. He is also the local principal investigator studying IGF-1 treatment and growth hormone treatment of children with IGF-1 deficiency.

Alberto Hayek, M.D.

Dr. Hayek is the Director of the Islet and Stem Cell Research Laboratory at the Whittier Institute. At the Institute, five independent investigators are pursuing studies encompassing human pancreas/islet development and islet cell replication:

• Pancreas and fetal islet development
• Transcriptional regulation in the developing islet
• Cell-to-cell interaction in the development of the human pancreas
• Extracellular matrix in islet development and function
• Epigenetic events in hESC and progenitor cells differentiation
• Proteomic studies in hESC and human adult and fetal islets
• Protocols for differentiation of pluripotent stem cells into insulin-producing cells
• The role of microRNAs in hESC differentiation
• Identification of small chemical compounds that promote islet cell proliferation

Ulupi Jhala, Ph.D.

Dr. Jhala's research is focused on unraveling the mechanisms that initiate and sustain beta cell death to result in diabetes. Current projects are focused on the role of mixed lineage kinases in initiating apoptosis in response to cytokines and fatty acids. Specific emphasis areas include regulation of mitochondrial bioenergetic pathways and how they impinge on cell survival. A second interest of research is understanding the role that epigenetic events play in the binary cellular decision of differentiation versus growth of the beta cell.

Kenneth Lee Jones, M.D.

Dr. Jones continues his interest in diabetes and obesity in children. He is currently studying the effect of sulfonylurea therapy on glycemic control and neuromuscular function in a child with the DEND syndrome and neonatal diabetes. He is also studying the misdiagnosis of type 2 diabetes in children .

Charles King, Ph.D.

Dr. King employs a proteomics-based approach to study islet biogenesis from pancreatic progenitor cells and human embryonic stem cells. He uses two-dimensional electrophoresis and mass spectrometry to map and identify global changes in protein expression patterns during differentiation. These techniques are combined with traditional biochemistry to study the role of protein interactions in PI 3-kinase-specific signal transduction as it relates to insulin signaling and cellular differentiation.

Karen Klein, M.D.

Dr. Klein is studying precocious puberty in girls with the goal of optimizing growth, exploring new treatment methods, and defining pubertal progression after treatment. Dr. Klein is also studying the effect of weight gain and racial diversity on pubertal onset. Her laboratory runs an ultrasensitive yeast bioassay for estradiol. This unique technique enables her to study estrogen’s role in growth and pubertal development in the above settings. A third area of research is adolescent polycystic ovarian syndrome. Dr. Klein shares laboratory space with Dr. Jeffrey Chang in reproductive endocrinology, and hopes to increase collaboration using his expertise and her patient population.

Anthony Montgomery, Ph.D.

Dr. Montgomery is studying the contribution of cell-adhesion molecules and the extracellular matrix (ECM) to both normal and pathogenic processes. He is currently focusing on the impact of integrin-ECM interactions on the derivation and function of human beta cells and on islet neogenesis. These studies are designed to improve our understanding of mechanisms regulating islet morphogenesis and to improve protocols for the ex vivo expansion of insulin-producing beta cells for transplantation. In collaboration with Drs. Alberto Hayek and Maike Sander, Dr. Montgomery is also developing novel approaches to increase the yield and function of insulin producing b-cells from both human embryonic stem cells (hESCs) and pancreatic progenitor populations. This work is focused on the use of small compound inhibitors of select non-receptor tyrosine kinases and upon the manipulation of the ECM environment. In addition to these studies, Dr. Montgomery has recently published a novel method for the derivation of Sertoli-like cells from hESCs. Sertoli cells are testicular cells that possess extraordinary immunomodulatory and trophic properties that allow them to support and protect both developing gametes and allogeneic transplants. Studies are planned to determine whether our hESCs-derived Sertoli cells can be used as a safe, unlimited, source of cells to provide support and immunoprotection for islet transplants. Finally, in separate studies, Dr. Montgomery is completing studies addressing the contribution of the neural cell adhesion molecule L1-CAM to the progression of malignant tumors.

Ron Newfield, M.D.

Dr. Newfield is developing a comprehensive database of endocrinology and diabetes patients seen at Rady Children’s Hospital-San Diego. The database has enabled two recently published manuscripts, and will remain a valuable source for future research in pediatric diabetes and endocrinology. One manuscript compared the dyslipidemia observed in non-diabetic obese children and adolescents versus those with type 2 diabetes, and the second manuscript described the rapid weight gain observed following diagnosis of type 1 diabetes in the context of the obesity epidemic. Dr. Newfield is involved in clinical trials of growth hormone treatment in children with cystic fibrosis, idiopathic short stature, and pharmokinetic studies of lipid-lowering medications. Dr. Newfield is also involved in a clinical trial now being launched, related to the immunomodulation of type 1 diabetes diabetes mellitus in recently diagnosed adolescents, by way of a vaccination with an islet-cell antigen.

Susan Phillips, M.D.

Dr. Phillips is focused on disordered fat metabolism in subjects with type 2 diabetes mellitus and/or insulin resistance. Her current studies involve the study of a novel secreted protein from fat that both enhances tissue response to insulin, as well as reducing the levels of inflammatory factors associated with the development of cardiovascular disease. Using a method she has developed for the culture of isolated human adipose tissue that maintains its metabolic phenotype over a seven-day culture period, Dr. Phillips is studying the synthesis and secretion of this protein. In this project, approved for the recruitment of 100 subjects, adipose tissue will be obtained during gastric bypass surgery from both the subcutaneous and visceral fat depots to determine if recognized differences in their metabolic behavior extend to the regulation of this novel protein. Dr. Phillips also continues her work in the area of adipose tissue - skeletal tissue cross talk with investigation into the modulation of gene expression in response to different conditions. These other projects include the study of cytokines released by diabetic and non-diabetic skeletal muscle, identifying their origin (myocellular vs. stromal) and their autocrine (on muscle tissue) and paracrine effect (on adipose tissue) glucose and lipid metabolism, as well as their regulation by insulin sensitizers.