Title:
Understanding pathways regulating liver versus pancreas fate decision and beta-cell regeneration

dc.contributor.advisor Storici, Francesca
dc.contributor.author Xu, Jin
dc.contributor.committeeMember Shin, Chong
dc.contributor.committeeMember Merrill, Alfred
dc.contributor.committeeMember Chernoff, Yury
dc.contributor.committeeMember Jang, Young
dc.contributor.department Biology
dc.date.accessioned 2018-08-20T15:30:24Z
dc.date.available 2018-08-20T15:30:24Z
dc.date.created 2017-08
dc.date.issued 2017-08-02
dc.date.submitted August 2017
dc.date.updated 2018-08-20T15:30:24Z
dc.description.abstract The liver and pancreas originate from common endodermal progenitors in early development. It has been shown that Bone morphogenetic protein 2b (Bmp2b) signaling is essential for determining the fate of these bipotential progenitors towards the liver or pancreas. Our goal was to identify Bmp2b-mediated gene regulatory networks and to delineate their underlying mechanisms governing the liver versus pancreas fate decision. From microarray assays, we found four and a half LIM domains 1b (fhl1b) as a novel target of Bmp2b signaling. We observed that fhl1b is primarily expressed in the prospective liver primordium. By loss- and gain-of-function analyses combined with a single cell lineage tracing technique, we showed that fhl1b favors the specification of liver and suppresses the induction of pancreatic cells. Diabetes is characterized by compromised glucose regulation. Both type 1 and type 2 diabetes patients suffer from losing functional β-cells along the progression of the disease. Our goal was to expand the understanding on pathways potentially promoting β-cell regeneration. First, given its function in suppressing pancreas induction with concomitant stimulation of liver, we conducted loss- and gain-of-function studies of fhl1b using a zebrafish model of type 1 diabetes. We conclude that fhl1b regulates the regeneration of β-cells mainly via modulating ductal progenitor-to-β-cell neogenesis. In addition, we identified TBK1/IKKε inhibitors (TBK1/IKKε-Is) as enhancers of β-cell regeneration through a chemical screening. We demonstrated that these inhibitors enhance β-cell-specific proliferation and further investigated the gene regulatory networks mediating mitogenic effects of TBK1/IKKε-Is. In collaboration with Dr. Oyelere and Dr. García at Georgia Institute of Technology, we further explored the specificity and potency of these inhibitors in mammalian systems (rat and human islet culture in vitro and a mouse model of type 1 diabetes in vivo) to complement our findings in zebrafish. We showed the conserved effects of increasing function and proliferation of β-cells in mammalian systems.
dc.description.degree Ph.D.
dc.format.mimetype application/pdf
dc.identifier.uri http://hdl.handle.net/1853/60155
dc.language.iso en_US
dc.publisher Georgia Institute of Technology
dc.subject Liver and pancreas
dc.subject Fate decision
dc.subject Progenitors
dc.subject Bmp2b
dc.subject Fhl1b
dc.subject Development
dc.subject Regeneration
dc.subject Diabetes
dc.subject Beta-cell
dc.subject TBK1/IKKε
dc.subject Proliferation
dc.subject Zebrafish
dc.subject In vivo
dc.subject Islet culture
dc.subject In vitro
dc.title Understanding pathways regulating liver versus pancreas fate decision and beta-cell regeneration
dc.type Text
dc.type.genre Dissertation
dspace.entity.type Publication
local.contributor.advisor Storici, Francesca
local.contributor.corporatename College of Sciences
local.contributor.corporatename School of Biological Sciences
relation.isAdvisorOfPublication 94282868-8eb6-4f1b-84b5-db8df7ae95a9
relation.isOrgUnitOfPublication 85042be6-2d68-4e07-b384-e1f908fae48a
relation.isOrgUnitOfPublication c8b3bd08-9989-40d3-afe3-e0ad8d5c72b5
thesis.degree.level Doctoral
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