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Contact Information

Batchelor Building 605
Ernesto-Bernal-Mizrachi

Ernesto Bernal-Mizrachi, M.D.

  • Professor
  • Chief, Division Endocrinology, Diabetes, and Metabolism Deputy Director of Beta Cell Biology and Signal Transduction Diabetes Research Institute Staff Physician Miami VA
Department:
  • Medicine
Research InterestPage 1
1. Neuroendocrine tumors. The work in this area centers in developing novel avenues to study neuroendocrine tumor biology. To this end, we have developed a novel model to study tumor biology using transplantation of human tissues into the anterior chamber of the mouse eye. We were awarded a pilot grant from Sylvester cancer center to assess this model in thyroid cancer. The support of Sylvester Cancer Center by this pilot grant led to securing R21 NIH funding by one of the members of my laboratory. We are now collaborating with Drs. Ivan and Komotar to start a similar program for pituitary tumors. FInally, we have already employed this model to study insulinomas in collaboration with Dr. Steven Rodgers. 2. Identification of novel pathways responsible for ?-cell proliferation. Developing pharmacological agents that expand ?-cells in vivo and in vitro and resist autoimmune injury could have major implications to cure T1D. During the last five years, Dr Bernal-Mizrachi has identified two other major pathways involved in ?-cell proliferation. The first pathway involves the enzyme protein L-isoaspartyl methyltransferase (PIMT). PIMT is highly expressed in human and rodent ?-cells and induction of this enzyme delays diabetes onset and reduces the severity of the disease in diabetes-prone BB rats. His laboratory has demonstrated that PIMT activation induces ?-cell proliferation by regulation of IRS2 levels, a critical molecule responsible for ?-cell proliferation and survival. The second pathway identified as important for ?-cell proliferation and survival is JNK3 signaling. He has shown that activation of this pathway can modulate ?-cell survival and proliferation by inducing IRS2 levels. Future experiments will validate these pathways as potential pharmacological targets and will design strategies to discover novel small molecules. These novel molecules could be used in translational experiments to treat diabetes by expanding ?-cell mass in vivo. 3. Pancreas plasticity, cell differentiation and cancer. The overall work in this area is to study the signaling pathways that regulate the differentiation program of the ?-cell. I have focused my studies in two major areas: 1. How insulin signaling modulates the pool of pancreatic and endocrine progenitors and 2. How insulin signaling regulates ?-cell dedifferentiation and eventually ?-cell failure. Using novel mouse models with gain of Akt signaling and lineage tracing analysis, my laboratory showed that activated Akt signaling is a major regulator of cellular plasticity and differentiation status of ?-cells. During the last few years Ithe Bernal-Mizrachi laboratory have explored how Akt signaling modulates ?-cell differentiation by assessing the role of c-myc and Notch signaling. In addition, identification of pathways that regulate differentiation of ?-cells could be used to generate functional ?-cell mass for the purpose of cell-based therapy. 4. Regulation of Akt/mTOR signaling and ?-cell regeneration. Previous work in the Bernal-Mizrachi lab demonstrated that activation of Akt signaling in ?-cells is critical for regulation of ?-cell proliferation and survival. During the last 15 years, Dr. Bernal-Mizrachi has build on these observations and identified that downstream of Akt, TSC2/mTOR signaling pathway is a critical pathway for ?-cells. The current work is dissecting the specific contribution of different components of the pathway by using in vitro studies and animal models. This knowledge will provide new platforms to develop novel pharmacologic strategies to induce controlled ?-cell mass by inducing selectively ?-cell proliferation without altering the risk of oncogenic transformation. These agents could be used in translational experiments to treat T1D by expanding ?-cell mass in vivo. At the same time, the pharmacologic manipulation of this pathway can be used to increase the pool of transplantable islets and enhance the success of islet transplantation. Another major impact of these studies is obtaining a better understanding of the effects of rapamycin in ?-cells mass and function. This is particularly interesting because rapamycin induced diabetes is a common complication of immunosuppressive therapy after transplantation. The work in this area has been supported by an NIH/NIDDK R01 for 15 years. 1. mTOR signaling in alpha-cells. Role in glucagon biology. Past effort has focused on the ?-cell, presenting diabetes as a unihormonal disorder. Contrary to this current approach, clinical data and animal experiments have shown that increased glucagon secretion by ?-cells play a role in the pathogenesis of hyperglycemia in type 1 and 2 diabetes. In T1DM, hyperglucagonemia induced by the lack of paracrine control from insulin has a major impact in the glycemic volatility, glucose control and increased susceptibility to hypoglycemia, a devastating complication of diabetes. During the last few years, his laboratory has been exploring how insulin signaling regulates the function and mass of ?-cells in vivo and the potential contribution of this process to the regulation of glucose homeostasis. Therefore, this research is significant because a better understanding of how glucagon secretion and ?-cell mass are regulated is critical to develop novel therapies for diabetes. These agents could be used in translational experiments to treat diabetes by controlling glucagon secretion. At the same time, the pharmacologic manipulation of this pathway can be used to increase the pool of ?-cells as a source to generate ?-cells. Another major impact of these studies is obtaining a better understanding of the effects of rapamycin in ?-cells mass and function. He has received VA funding for this area of investigation.