Programmed cell death (PCD) is an important process necessary for the maintenance of tissues in adult organisms and the crafting of distinct tissues in development. The two main types of PCD, apoptosis and necroptosis (i.e. programmed necrosis), are characterized through differing morphologic presentations and outcomes. Death receptor signaling is a context in which both apoptotic or necroptotic outcomes can occur. Several recent studies implicate proteins involved in apoptotic signaling in the inhibition of necroptosis including Caspase-8, FADD, and cFlipL. Bid, a member of the BCL-2 family of proteins, is cleaved by Caspase-8 which promotes its activation and translocation to the mitochondrion, promoting apoptosis. To evaluate what role Bid might play in the necroptotic arm of death receptor signaling we developed a mouse with Bid and its apoptotic arm of function (Bax and Bak) removed in hematopoietic cells. Loss of these three proteins leads to loss of restraint of necroptosis leading to increased necroptotic death, inflammatory signaling, and perturbation of tissue homeostasis in the hematopoietic and gastrointestinal organ systems. These findings in mice have implications for Myelodysplastic Syndrome, a bone marrow failure disorder characterized by increased PCD, and Inflammatory Bowel Diseases, inflammatory diseases characterized by overwhelming inflammation in the gastrointestinal system.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11062016-103445 |
| Date | 18 November 2016 |
| Creators | Wagner, Patrice Nicole |
| Contributors | Sandra Zinkel, Mark P. DeCaestecker, William P. Tansey, Mark R. Boothby, Stephen J. Brandt |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-11062016-103445/ |
| Rights | restrictsix, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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