Type 1/Childhood-Onset Diabetes

Robert S. Sherwin, M.D. (Endocrinology) Dr. Sherwin’s lab focuses on: 1) the mechanisms for hypoglycemia unawareness in T1DM and 2) the beta cell targets of autoimmune attack in T1DM. Currently, the lab is studying the involvement of VMH KATP-channel activity, GABA neurotransmission, AMP-kinase activity, and corticotrophin-releasing factor receptor 2 in the central response to hypoglycemia. Other studies examine the effect of insulin on brain function as well as the changes in brain fuel transport and metabolism caused by acute and recurrent hypoglycemia. The Sherwin lab has also cloned several T cell lines from NOD mice that recognize defined beta cell autoantigens and influence disease progression. Ongoing studies are examining the contribution of new islet autoantigens to the immunopathogenesis of diabetes and the development of T1DM in humanized HLA-DQ8 transgenic mice.

Alfred Bothwell, Ph.D. (Immunobiology) The research goals of the Bothwell lab are to characterize the development and function of T cells and to characterize mechanisms that affect T cell recognition and recruitment into vascular sites. His experience with synthetic microvessels has led to translational projects to revascularize human or porcine islets to treat T1DM. There is a strong commitment to the development of humanized mouse models to study human lymphocyte interactions with a variety of cell types, including islets. More recently his laboratory is using human CD34+ progenitors to reconstitute a more complete human hemopoietic system in mice.

Richard Flavell, Ph.D. (Immunobiology, HHMI) Dr. Flavell’s laboratory studies the molecular and cellular basis of the immune response. This laboratory has been instrumental in discovering the molecular basis of T-cell differentiation from precursor cells into generally differentiated subsets as well as elucidating the mechanisms whereby the immune response is regulated, so that autoimmunity is prevented and overaggressive responses to pathogens controlled. Dr. Flavell’s laboratory has also discovered the role of several receptor families in the innate immune response, including Toll-like receptors and intracellular Nod-like receptor families (NLRs). Dr. Flavell’s laboratory has been studying the role of TGF-? in the development of regulatory CD4+ T cells that can modulate autoimmune diabetes. These studies have shown that a transient pulse of TGF-? in the islets during the priming phase of diabetes is sufficient to inhibit disease onset by promoting the expansion of intra-islet CD4+CD25+ Foxp3+ T cells.

Kevan Herold, M.D. (Endocrinology) Dr. Herold’s research interests involve the pathogenesis and treatment of autoimmune disease, in particular Type 1 diabetes. Studies involve clinical trials with patients and investigations of the mechanism of action of immune therapies and the pathogenesis of disease in patients as well as in animal models when needed to address what cannot be studied in humans. Over the past 7 years, Dr. Herold’s lab has carried out trials of a humanized non-FcR binding anti-CD3 monoclonal antibody in type 1 diabetic patients and has studied the mechanism of its action. These clinical studies have suggested novel mechanisms of immune regulation that are now to be addressed with new clinical studies.

Rory McCrimmon, M.D. (Endocrinology) The primary research interest in Dr. McCrimmon’s laboratory is to explore the underlying mechanisms by which the brain, and in particular specific hypothalamic nuclei, sense a falling blood glucose and trigger a neuroendocrine stress response. They are also interested in studying factors that modulate the neuroendocrine stress response in order to try and understand why this system is impaired in diabetes. Finally, his lab is interested in the central (primarily hypothalamic) regulation of peripheral metabolism, energy balance and body weight.

Scott Rivkees, M.D. (Pediatric Endocrinology) Dr. Rivkees’ research program focuses in three major areas: circadian biology, adenosinergic influences on brain injury of prematurity and the discovery of novel pediatric diagnostics and therapeutics. He discovered that A1 adenosine receptor activation induces periventricular white matter injury (PWMI)-the most common neurological disorder affecting premature infants. This work with adenosine receptors has also shown important effects of these receptors on modulating neuronal sensitivity to hypoglycemia. Most recently, high-throughput screening is being applied to identify stimulators of oligodendrocyte development, as a potential treatment of white matter disease.

William Tamborlane, M.D. (Pediatric Endocrinology) Dr. Tamborlane’s principal area of interest is in the development of new technology and therapeutics for children with Type 1 diabetes (T1DM). Studies are evaluating whether recent advances in continuous glucose monitoring technology can be utilized to reduce severe hypoglycemia, while simultaneously improving overall diabetes control in youth with T1DM. Yale is one of the 5 clinical centers in the NICHD Diabetes Research in Children Network (DirecNet) whose major aim is to study the use of glucose sensing systems in children with T1DM. Dr. Tamborlane’s group recently completed the first phase of studies that demonstrated the feasibility and short-term inpatient efficacy of an artificial pancreas system that utilizes external sensors and insulin pumps and a series of follow-up inpatient studies are in progress in preparation for ultimate outpatient use of closed-loop insulin delivery systems.

Li Wen, M.D., Ph.D. (Endocrinology) Dr. Wen’s laboratory studies the immunopathogenesis of Type I Diabetes Mellitus. She is interested in the contribution of specific HLA genes to islet autoimmunity and her laboratory has developed several novel transgenic models of susceptibility or resistance to diabetes by expressing specific HLA-DQ or HLA-DR haplotypes in mice. Ongoing studies are using these “humanized” models of disease susceptibility or resistance to study the effects of interacting genes on autoimmunity and to develop novel immune modulatory therapies for diabetes.