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Title: Senescence-associated inflammation : mechanistic insights into IL-1 processing and the role of senescence in alternative liver growth
Author: Dewhurst, Matthew
ISNI:       0000 0004 7658 6853
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2019
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Cells do not divide indefinitely. Rather, a cell enters a state of permanent cell cycle arrest termed senescence. Senescence is induced by DNA damage resulting from telomere shortening (replicative exhaustion), oncogenic transformation or oxidative stress. Senescence provides a mechanism by which cells autonomously detect and halt the progression of oncogenic transformation. However, accumulation of senescent cells reduces the integrity of a tissue. Therefore, senescent cells need to be cleared by phagocytic immune populations to maintain tissue homeostasis. Senescent cells express a pro-inflammatory secretome to induce phagocytic clearance and promote subsequent tissue remodelling. This senescence-associated inflammation is an example of sterile inflammation and is regulated by the cytokine IL-1α. IL-1α exists in both an unprocessed and mature form. Both are biologically active but display differential cellular localisation. The effect of cellular localisation on IL-1α function is not fully understood and may be important for the regulation of senescence. Chronic liver diseases are associated with accumulation of senescent hepatocytes, the constituent cell type of the liver. As a result, the regenerative capacity of the liver is impaired. Alternative mechanisms of liver growth activate in the absence of hepatocyte division, including the expansion of a putative niche of hepatic progenitor cells. However, the extent to which hepatic progenitor cells reconstitute new populations of hepatocytes is controversial and the signals regulating progenitor cell expansion and differentiation remain poorly understood. This thesis sought to investigate the mechanistic regulation and functional significance of senescence-associated inflammation. It has investigated the effect of IL-1α cellular localisation on the senescent phenotype. Furthermore, it has developed an in vivo model of widespread hepatocyte senescence which recapitulates key characteristics of chronic liver disease. Finally, it has identified for the first time that hepatic progenitor cells express the receptor IL-1R1 and that differentiation of hepatic progenitor cells requires IL-1 signalling.
Supervisor: Swanton, Eileithyia ; Brough, David Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available