dc.creator | Clayton, Hannah Worchel | |
dc.date.accessioned | 2020-08-21T21:02:41Z | |
dc.date.available | 2017-02-24 | |
dc.date.issued | 2017-02-24 | |
dc.identifier.uri | https://etd.library.vanderbilt.edu/etd-02202017-135410 | |
dc.identifier.uri | http://hdl.handle.net/1803/10597 | |
dc.description.abstract | Reprogramming of pancreatic cells into new beta-like cells is a potential therapy for Type 1 diabetes. Pancreatic acinar cells are an appealing target for cellular reprogramming since they are abundant, derived from a common progenitor cell during pancreatic organogenesis, and exhibit significant transcriptional plasticity. Towards this end, it has been reported that adenoviral-mediated expression of three pancreas-specific transcription factors MafA, Pdx1 and Neurog3 (3TF) in immunocompromised Rag1-/- mice resulted in the conversion of pancreatic acinar cells into new, insulin-secreting, beta-like cells. Using a transgenic mouse model to express 3TF in a pancreatic acinar cell- and doxycycline-dependent manner, we discovered that the outcome of transcription factor-mediated acinar to beta-like cellular reprogramming is dependent on both the magnitude of 3TF expression and on reprogramming-induced inflammation. Overly robust 3TF expression causes acinar cell necrosis resulting in marked inflammation and acinar-to-ductal metaplasia. Generation of new beta-like cells requires limiting reprogramming-induced inflammation, either by reducing 3TF expression or by eliminating macrophages. The new beta-like cells were able to reverse streptozotocin-induced diabetes 6 days after inducing 3TF expression but failed to sustain their function after removal of the reprogramming factors. | |
dc.format.mimetype | application/pdf | |
dc.subject | acinar-to-ductal metaplasia | |
dc.subject | Reprogramming | |
dc.subject | inflammation | |
dc.subject | beta cells | |
dc.subject | acinar cells | |
dc.subject | diabetes | |
dc.title | Variables that influence transcription factor-mediated acinar to beta cell reprogramming | |
dc.type | dissertation | |
dc.contributor.committeeMember | Roland W. Stein | |
dc.contributor.committeeMember | William P. Tansey | |
dc.contributor.committeeMember | Luc Van Kaer | |
dc.type.material | text | |
thesis.degree.name | PHD | |
thesis.degree.level | dissertation | |
thesis.degree.discipline | Cell and Developmental Biology | |
thesis.degree.grantor | Vanderbilt University | |
local.embargo.terms | 2017-02-24 | |
local.embargo.lift | 2017-02-24 | |
dc.contributor.committeeChair | Gu Guoqiang | |