This thesis explores the operation of third sector politics within the changing context of local governance. Throughout the history of urban policy the concept of community has fonned a recurrent, if fluctuating theme (Eisenschitz and Gough, 1993; Raco, 1998a). Recent literature has tended to assume the emergence of a new local governance characterised by restructured local political relations. A related strand of thinking suggests that within this new context, the community role has been elevated. The recent turn to community seems to present a vision in which public participation is something of a panacea to secure successful and lasting urban regeneration and more effective local governance. The tendency within the literature has been to focus on new institutional configurations rather than the detailed operation of the new arrangements. This thesis seeks to assess in detail how the third sector is engaging in processes of local governance and the mechanisms that support this. The research focuses on the fine-grain of spatial and institutional representation of community interests and the fonn and function of community politics. It develops this focus through a specific concern with the operation of community politics and the constitution of governance roles through two in-depth case studies conducted in the North-East. These provide contrasting examples of third sector organisation and coordination, thus highlighting the locally distinctive nature of third sector politics. The thesis concludes that attempts at specifying changing local governance and models of community engagement have tended to ignore the complexity of community politics. Therefore, it is argued that future theoretical developments need to address these complexities in order to capture any change in the fonn and nature of local political relations in general and third sector politics in particular.

During hepatic disease the liver has the unrivalled ability to regenerate, by activating mature hepatocytes which can divide and thereby reconstitute the functional liver mass. However in the context of chronic hepatocellular disease the liver can regenerate from an endogenous population of hepatic progenitor cells (HPCs). The mechanisms which are involved in the activation and differentiation of these HPCs is not fully understood. To investigate whether there is a differential signalling requirement in HPCs acquiring a biliary versus hepatocellular fate we established in the laboratory two models of chronic liver damage and regeneration, one of which causes hepatocellular death, and results in infiltrating HPCs regenerating hepatocytes, and a second which causes biliary blockage and death, resulting in biliary regeneration. Here we describe how during biliary regeneration the Notch signalling pathway is highly expressed and activated. HPCs cells are consistently associated with a myofibroblast niche which expressed the ligand Jagged-1 at high levels. We have modulated the Notch signalling pathway in both a co-culture system and our models in vivo to demonstrate that Notch signalling is important in the specification of biliary cells, and that inhibition of this pathway both in vitro and in vivo results in the abrogation of biliary commitment. During hepatocellular regeneration we have found that the negative repressor of Notch signalling Numb is highly expressed in tandem with a low expression of the Notch pathway. We suggest that Wnt signalling maintains Numb within these HPCs at a high level and that this, along with stimulation of a hepatocellular programme allows HPCs to exit from a biliary fate and assume a hepatocellular phenotype. Finally we have found that macrophage ingestion of debris promotes the expression of Wnt, and that ablation of these cells results in a phenotypic switch between HPCs assuming a hepatocellular fate and a biliary one.

No description available.

Bioelectric fields are involved in patterning during embryonic development and play roles in regenerative growth and wound healing. Planaria are flatworms capable of regenerating whole new intact organisms from tiny portions of tissue, owing to a widespread population of adult somatic stem cells known as neoblasts. Previous research has suggested that an endogenous bioelectric field may contribute to the control of axial polarity and regenerative fate during planarian regeneration. By establishing novel techniques, we further investigated this hypothesis in experimentally relevant planarian species Dugesia japonica and Schmidtea mediterranea. Techniques were developed to measure transepithelial potential (TEP), record epithelial ion transport and apply exogenous electric fields to test the hypothesis that an endogenous electrical gradient contributes to axial regenerative polarity in planaria. We found that in the mesenchymal spaces of Dugesia japonica and Schmidtea mediterranea, a voltage gradient exists such that the head region is more negative than the tail. Importantly, this voltage gradient is maintained in regenerating amputated tissue fragments. Disrupting this endogenous electric field by means of exogenous DC electric field application induced regenerative anomalies affecting the anteroposterior axis. Reversal of the TEP gradient and regenerative polarity was achieved by application of an electric field that opposed the direction of the worm's natural electrical polarity, suggesting that the natural electrical gradient contributes to the control of polarity establishment during planarian regeneration.

Each year the Organ Procurement and Transplantation Network (OPTN) reports an increase in patients requiring an organ transplant without an increase in available donor organs, leading to a transplant gap that continues to widen. Over 70% of donor hearts are deemed unsuitable for transplantation each year, and a large number of these organs (~50%) are discarded due to poor organ function, decreased ejection fraction, disease, or cardiac arrest (Scientific Registry of Transplant Recipients (SRTR) Annual Data Report 2011).We therefore set out to improve knowledge in the field of cardiac transplantation in terms of organogenesis, bioenergetics, and regeneration. The main goal through tissue bioengineering is to regenerate and salvage discarded hearts through organogenesis, or to lengthen the total organ preservation time such that organs would not be thrown away while a recipient was waiting to be found. Our first hypothesis was that an optimized acellular extracellular matrix scaffold would allow for cell adherence, growth and proliferation, and could potentially be grown into a clinically transplantable organ. To achieve these goals, an optimized protocol was developed for the total acellularization of a whole porcine heart, leaving behind a 3D bioscaffold. We showed that acellularized matrices could be successfully seeded using endothelial cells for acellular vasculature and stem cells for other acellular tissues, both as a 2D matrix and within a constantly perfused 3D Langendorff setup bioreactor. In order to best understand cell-cell and cell-matrix interactions, cellular bioenergetics were evaluated. We hypothesized that the bioenergetic demand of the type and anatomical origin of stem cells would affect the regeneration potential dependent on intrinsic metabolic demand. We therefore showed a differential of the bioenergetic profiles of human adipose-derived stem cells isolated from various adipose depots, concluding that the physiological microenvironment that supports stem cells in specific anatomic locations can regulate how stem cells participate in tissue regeneration, maintenance and repair, and also will vary based on donor-differences. During organ transplantation, organ preservation solutions are created for use at specific conditions, such as on ice or at room temperature. We hypothesized that hypothermia would slow down cellular metabolism, and that solutions containing a higher content of antioxidants and other protective substrates against ischemic reperfusion injury would create the best organ storage conditions. We tested three organ preservation solutions against control media and normal saline at 4 and 21 degrees C, for 4 to 8 hours, investigating the bioenergetics of organ preservation solution effects on cardiac cells. By simulating clinical conditions, we were able to determine that one of our solutions was ideal and had protective effects for cells for up to 8 hours at 4 degrees C. Finally, we believed that studying existing cardiac patches and optimizing cardiac matrix design would lead to improved cardiac physiological function and would aid in healing and repair during cardiac surgery. Following a clinical case report showing new cardiac tissue growth after implantation of an acellular porcine extracellular matrix, we devised a proof-of-concept study to show that clinical matrices could be easily cultured in vitro. We successfully seeded these clinical matrices using human amniotic stem cells, a commonly used cell type for regeneration and repair after surgery. Our preliminary studies suggest that preconditioned matrices can be potentially used clinically for greater efficacy and tissue regeneration.

published_or_final_version / Biochemistry / Doctoral / Doctor of Philosophy

published_or_final_version / Anatomy / Doctoral / Doctor of Philosophy

published_or_final_version / Biochemistry / Master / Master of Philosophy

published_or_final_version / abstract / Medicine / Master / Master of Research in Medicine

published_or_final_version / Dentistry / Doctoral / Doctor of Philosophy