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Title page for ETD etd-11062016-103445


Type of Document Dissertation
Author Wagner, Patrice Nicole
URN etd-11062016-103445
Title Proapoptotic Bid inhibits the Execution of Programmed Necrosis Affecting Hematopoietic and Intestinal Homeostasis
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Mark P. DeCaestecker Committee Chair
Mark R. Boothby Committee Member
Sandra Zinkel Committee Member
Stephen J. Brandt Committee Member
William P. Tansey Committee Member
Keywords
  • Apoptosis
  • BCL-2 Family
  • Hematopoiesis
  • Intestinal homeostasis
  • Programmed Cell Death
  • Necroptosis
Date of Defense 2016-09-15
Availability unrestricted
Abstract
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.
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