Gannon Lab

Research Topic:

 FoxM1, a transcription factor that promotes cell cycle progression, is expressed exclusively in proliferating cells. Murine FoxM1 is required for postnatal beta cell expansion and beta cell proliferation after partial pancreatectomy and during pregnancy.

 In both rodents and humans, the capacity of beta cell replication diminishes with age. This reduction correlates with a decrease in Foxm1 expression. To determine whether increased FoxM1 activity can rejuvenate the replicative potential of beta cells, I am generating transgenic mice that express an inducible, hypermorphic form of FoxM1 in the beta cell. To investigate the factors that are expressed differentially in proliferating beta cells compared to quiescent beta cells, I am deriving a mouse that expresses an RFP-tagged version of FoxM1 within the endogenous Foxm1 locus. These mice will be crossed to MIP-GFP mice, and doubly fluorescent (proliferating beta cells) as well as green fluorescent cells (non-proliferating beta cells) will be isolated by FACS. RNA from both populations will be analyzed by microarray.

See Publications here.

Research Topic:

Beta cell mass expands during times of metabolic need, such as during pregnancy and obesity.  Failure of beta cell mass expansion in response to metabolic demands can result in diabetes.  Therefore, understanding the mechanisms whereby proliferative signals impact beta cells is a crucial area of diabetes research.  One important tissue factor necessary for proliferation in post-natal beta cells is the FoxM1 transcription factor.

Our lab has previously shown that murine FoxM1 is needed for beta cell proliferation during pregnancy and after partial pancreatectomy; however, we do not know the role of FoxM1 in beta cell proliferation that occurs as a result of obesity.  One aspect of my project is to determine if FoxM1 has a role in beta cell expansion in mice in response to a high fat diet.  In order to address this question, I am using mice in which FoxM1 can be conditionally deleted from the beta cells and exposing them to high fat diet.    In addition, I am interested in understanding how FoxM1 is transcriptionally regulated by proliferative stimuli in beta cells.  I am using cultured beta cell lines and isolated islets to determine which secondary messenger pathways are utilized to regulate the transcription of FoxM1 and its activity in response to proliferative stimuli.  

Research Topic:

During pregnancy, the developing fetus creates an increased demand for insulin that requires compensatory actions to support maternal health. These adaptations are achieved as a result of beta cell expansion, improved sensitivity to glucose, and enhanced glucose stimulated insulin secretion within the maternal islets. Failure of these actions to occur results in gestational diabetes mellitus (GDM), a condition that occurs in 3-7% of pregnancies and is characterized by high maternal blood glucose levels and an increased risk of preeclampsia and C-sections, as well as increased risk for Type 2 diabetes later in life for both mother and fetus. Our data indicates that CTGF, a protein with known roles in embryonic beta cell proliferation, is re-expressed in maternal beta cells during pregnancy, and pregnant mice with haploinsufficiency of CTGF display impaired glucose tolerance, similar to GDM. Using mutant CTGF alleles, I aim determine what role CTGF plays in the increase in beta cell proliferation, improved sensitivity to glucose, and enhanced GSIS that occurs during pregnancy. Furthermore, CTGF has known effects on the TGF-beta, BMP, and Wnt signaling pathways. As such, I will use reporter mice as well as commercially available assays to determine if CTGF influences these pathways to mediate glucose clearance during pregnancy.