Roles
Professor of Medicine
Chief, Division of Endocrinology, Diabetes and Metabolism
Deputy Director of Beta Cell Biology and Signal Transduction
Secondary Appointment of Biochemistry and Molecular Biology
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Biography
His research over the last 15 years has focused on the regulation of pancreatic beta cell mass and function, with a particular interest in Akt and mTOR signaling pathways in beta cell proliferation. His laboratory has made major contributions to our understanding of signaling pathways that regulate beta cell expansion and survival. The long term goal of these signaling studies is to develop novel pharmacological agents for the treatment and cure of type 1 and 2 diabetes. In addition, his laboratory also explores how the fetal environment can alter the susceptibility to diabetes later in life, a concept that has major implications to human diabetes. Finally, his group has been exploring the importance of glucagon and alpha cells in the regulation of glucose homeostasis with particular interest in discovering avenues to decrease hypoglycemia in diabetes. -
Education & Training
Education
Licensures and Certifications
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Honors & Awards
No result found
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Teaching Interests
He has an excellent record of grant funding and currently is principal investigator on RO1 grants from the National Institutes of Health, a VA MERIT award and two foundation grants including American Diabetes Association and Juvenile Diabetes Research Foundation. He has mentored over 15 undergraduate students and postdoctoral fellows, many of whom are now highly successful academic scientists and physicians. He has been consistently active in postdoctoral education and has served on the fellowship Training Operating Committee at Washington University and The University of Michigan. In addition, he has served on study sections and review panels for the National Institutes of Health and the Juvenile Diabetes Research Foundation. He has also is a member of the editorial board of the American Journal of Physiology- Endocrinology and Metabolism and ad hoc reviewer for various specialty journals, Diabetes, Cell Metabolism, Diabetologia, Nature Medicine, Scientific Reports, Science, Gastroenterology, the Journal of Clinical Investigation, Cell Metabolism and Annual Review of Physiology. Dr. Bernal-Mizrachi has received many wards including a Junior Faculty Award and a Career Development Award from the American Diabetes Association and he was elected a member of the American Society for Clinical Investigation (ASCI). -
Research Interests
Pancreatic ß-cell Biology The long-term goal of this research program is to determine the signaling pathways and molecular mechanisms involved in the regulation of ß-cell mass. The objective of the research in this area is to delineate the molecular mechanisms, downstream signaling pathways and critical components involved in PI3K/Akt–dependent regulation of G1-S transition, proliferation and mass of ß-cells. Our central hypothesis is that the PI3K/Akt pathway regulates ß-cell proliferation and mass by regulating protein levels, expression, cellular localization and activity of cell cycle components involved in G1 to S transition. The rationale for the proposed research is that, once the understanding of downstream elements involved in PI3K/Akt induced ß-cell proliferation is obtained, it is expected that it may become possible to identify new pharmacologic targets to treat and prevent type 2 diabetes, and increase the number and survival of ß-cells for transplantation. The use of transgenic mice expressing a constitutively active Akt in islet ß-cells under the control of the insulin promoter (caAktTg) will allow us to make a very careful dissection of downstream events in vivo. To study ß-cell proliferation, we will examine the mechanisms involved in regulation of the cell cycle in pancreatic ß-cells focusing in the role of cdk4 and its major regulators, p27, p21 and cyclin D. These studies will be performed in animal models and complemented with in vitro experiments in insulinoma cell lines. Another important area of investigation is the role of nutrient signaling pathways downstream of mTOR in ß-cell growth. These experiments will be performed in animal models with gain and loss of function of the ribosomal S6 protein kinase (S6K). The role of these genes in apoptosis and in stress conditions such as fat feeding and transplantation will be also evaluated.
Pancreas DevelopmentThe overall goal of this area is to study the signaling pathways that regulate the differentiation program of pancreas. This work will attempt to increase the pool of pancreatic and endocrine progenitors by activating self-renewal and proliferation of progenitor cells. These studies could lead to identification of potential targets for novel therapeutic approaches that could increase the generation of ß-cells in vivo and in vitro. These experiments will potentially produce cells that could be used in the transplantation model.
Islet Transplantation One potential approach to improve the success and overcome the limited source of islets for transplantation is to increase the capacity of islets to proliferate and resist injury. The main goal in this area will be to study the mechanisms involved in regulation of transplanted ß-cell mass and to generate ß-cells that could be maintained in culture and will be resistant to injury after transplantation. To achieve this, we have generated tetracycline inducible transgenic animals with regulatable Akt activity. The response of islets from these mice to transplantation using different temporal patterns of Akt induction will be studied. This model will also be used as a phenotyping tool to evaluate the role of specific genes in the regulation of -cell mass, proliferation and apoptosis. The proposed studies will generate the information to develop therapeutic strategies aimed to protect the transplant and decrease the amount of tissue used for transplantation.
Novel Akt targets in pancreatic ß-cellsIdentification of novel Akt targets in ß-cells is significant because it will delineate potential downstream signaling events and components mediating proliferative responses that lack oncogenic potential. This is expected to have a positive impact for the design of pharmaceutical agents that will induce selectively ß-cell proliferation without altering the risk of oncogenic transformation. To identify novel Akt targets, we are performing microarray experiments in islets and cell line with gain of Akt fun -
Publications
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