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Research
Welcome to Dr. Bernal-Mizrachi’s Beta Signaling Lab where our multidisciplinary research spans Pancreatic β-cell Biology, Pancreas Development, and Islet Transplantation to unravel the intricate mechanisms governing diabetes pathogenesis and pioneer transformative therapies.
Pancreatic β-cell Biology
The long-term goal of this research program is to determine the signaling pathways and molecular mechanisms involved in the regulation of β-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 β-cells. Our central hypothesis is that the PI3K/Akt pathway regulates β-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 β-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 β-cells for transplantation. The use of transgenic mice expressing a constitutively active Akt in islet β-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 β-cell proliferation, we will examine the mechanisms involved in regulation of the cell cycle in pancreatic β-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 β-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 Development
The 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 β-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 β-cell mass and to generate β-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.