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Title page for ETD etd-03312010-163151


Type of Document Dissertation
Author Zhang, Jia
Author's Email Address jia.zhang@vanderbilt.edu
URN etd-03312010-163151
Title The role of Foxm1 in growth factor-mediated pancreatic beta-cell proliferation
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
David M. Miller Committee Chair
Anna L. Means Committee Member
Maureen A. Gannon Committee Member
Patricia A. Labosky Committee Member
Stacey S. Huppert Committee Member
Keywords
  • gestational diabetes
  • beta-cell proliferation
  • Foxm1
Date of Defense 2010-03-08
Availability unrestricted
Abstract
THE ROLE OF FOXM1 IN GROWTH FACTOR-MEDIATED PANCREATIC BETA-CELL PROLIFERATION

JIA ZHANG

Dissertation under the direction of Professor Maureen A. Gannon

Both type I and type II diabetes are due to an either absolute or relative loss of â-cell mass. A thorough understanding of â-cell mass regulation is needed for treatment of diabetes by restoring â-cell mass and glucose homeostasis. In adults, â-cell mass is replenished mainly through â-cell proliferation. Growth factors such as placental lactogen (PL), insulin-like growth factor-1 (IGF-1) and hepatocyte growth factor (HGF) are potent â-cell mitogens. However, little is known about the intrinsic factors within a â-cell that mediate the mitogenic effects of growth factors. In searching for those intrinsic factors, previous studies from our laboratory have demonstrated that Foxm1, a pro-proliferation transcription factor, is required for the maintenance and expansion of adult â-cell mass under basal conditions and in injury models. This dissertation examined the hypothesis that Foxm1 plays a central role downstream of one or multiple growth factors to stimulate â-cell proliferation. The pregnancy hormone PL is mainly responsible for increased â-cell proliferation in pregnancy. We found that Foxm1 was up-regulated in maternal islets during pregnancy and PL induced Foxm1 expression in cultured islets. Additionally, Foxm1 was required for PL-mediated â-cell proliferation in vivo. Our preliminary data further identified Foxm1 as a novel direct target of the transcription factor Stat5, a downstream effector of PL signaling. To determine whether Foxm1 is essential for increases in â-cell proliferation and mass during pregnancy, we evaluated female mice with a pancreas-wide Foxm1 inactivation (Foxm1Äpanc). These mice developed gestational diabetes. Compared to controls, Foxm1Äpanc mice exhibited blunted â-cell proliferation and mass in response to pregnancy, which is likely due to the elevated islet expression or activity of two cell cycle inhibitors, Menin and p27. Foxm1-mediated â-cell proliferation is thus crucial for â-cell mass expansion and glucose homeostasis during pregnancy.

Our ongoing endeavors include examining whether Foxm1 is required for HGF and IGF-1-stimulated â-cell proliferation. In conclusion, the central role of Foxm1 in â-cell maintenance and growth factor stimulated-growth makes it a promising therapeutic candidate for enhancing â-cell mass in vivo.

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