Injuries to the central nervous system are irreversible and debilitating due to the limited regrowth of damaged or severed neurons. Two small molecules, xanthofulvin and vinaxanthone, isolated from P. vinaceum and P. glabrum promote spinal cord regeneration in animal models. It is speculated that these natural products inhibit semaphorin 3A, a chemorepellent that mitigates axonal growth-cone formation. In addition to promoting axonal growth, rats treated with vinaxanthone and xanthofulvin following complete spinal cord transection experienced greater remyelination, increased angiogenesis, attenuated apoptosis, and depressed scaring of the lesion site. The only prior synthesis of vinaxanthone speculated that the xanthone core is constructed via enzyme-catalyzed intermolecular Diels-Alder reaction. We have demonstrated, however, that warming a functionalized acetoacetyl chromone in water, furnishes vinaxanthone in good yield, providing an alternative biosynthetic pathway. With a robust syntheses of both natural products, we determined the protein target of the observed regeneration: succinate receptor 1, providing a new therapeutic target to promote neuronal regeneration. Among the various methods of incorporating oxygen into aryl rings, the direct conversion of a C-H bond into a C-OH bond is ideal. The metal-free hydroxylation of arenes developed in our laboratory, utilizing phthaloyl peroxide, marks the first disclosure of this transformation using mild conditions. Computational and experimental evidence obtained thus far has supported a mechanism involving a diradical intermediate. The reactivity of phthaloyl peroxide was increased by the incorporation of two chlorine atoms onto the ring. To minimize the accumulation of large quantities of peroxide, the optimization of the preparation of the peroxide in flow has been developed. This protocol immediately consumes the peroxide as it is generated. Finally, a new dearomatization reaction has been optimized. This reaction forms two carbon-oxygen bonds and dearomatizes the ring system.

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Hematopoietic Stem Cells (HSCs) are characterized by their ability to both self-renew and give rise to all lineages of the blood system. A recent chemical genetic screen identified 17β-estradiol (estrogen) as a novel modifier of the expression of the conserved HSC markers runx1 and cmyb in the Aorta-Gonad-Mesonephros of developing zebrafish. Exposure to exogenous estrogen during the development of the hematopoietic niche impeded specification of hemogenic endothelium and the subsequent emergence of HSCs via antagonism of somitic-derived VEGF signaling. Conversely, inhibition of endogenous estrogen activity increased the number of functional HSCs present in the embryo and resulted in higher expression of VEGF target genes, suggesting that endogenous estrogen acts to define the ventral limit of VEGF activity and hemogenic endothelial specification. In contrast, when embryos were exposed to estrogen after niche specification, markers of HSCs were increased, indicating that estrogen has a biphasic effect on HSC formation; this effect appears to be at least partially mediated by enhanced cell cycling of the HSC population. Estrogen exposure during primitive erythropoiesis likewise increased the number of erythroid progenitors in the embryo, but their maturation into functional erythrocytes was impaired. Inhibition of erythrocyte maturation is also conserved in a mammalian model of in utero excess estrogen, causing propensity for embryonic lethality. Treatment of adult zebrafish with exogenous estrogen after ablation of the hematopoietic system by irradiation revealed that elevated estrogen levels improved hematopoietic regeneration. Consistent with a role for hormonal regulation of HSC homeostasis, accelerated recovery of hematopoietic stem and progenitor numbers was observed in female fish compared to males, suggesting an endogenous difference in regenerative capacity between the sexes. Together, these data identify multiple distinct roles for estrogen in HSC biology and indicate it is a physiologically relevant regulator of HSC development and homeostasis.

The research project, The Enzymatic Synthesis of CoA Derivatives Using a New ATP Regeneration System, describes the multiple lab trials conducted to develop an ATP regeneration system using various concentrations of specific substrates and the two enzymes MatB and PrpE. Reactions were combined using different concentrations of ADP, the addition or removal of ADK (adenylate kinase), and the substitution of either MatB or PrpE. Further reactions were combined using trans-crotonyl, trifluoroacetic acid, butyric acid, acetic acid, and creatine phosphokinase. This report also includes the methods used and analysis of the different chromatographs of each sample tested. / text

Severe extremity trauma often involves significant damage to multiple tissue types, including bones, skeletal muscles, peripheral nerves, and blood vessels. Such injuries present unique challenges for reconstruction, and improving structural and functional outcomes of intervention remains a pressing, unmet clinical need. While tissue engineering/regenerative medicine (TE/RM) therapeutics offer promising potential to overcome the status quo limitations of surgical reconstruction, very few products have transitioned to clinical practice. Improving treatment options will likely require advancing our understanding of the biological interactions occurring in the repair of damaged tissues. Bone tissue is known to be innervated and highly vascularized, and both tissue types are involved in normal bone physiology. However, the degree to which these tissue relationships influence the repair of large, multi-tissue defects remains unknown. Accordingly, the goal of this thesis was to investigate tissue regeneration in two novel composite injury models. First, we characterized interactions in a composite bone and nerve injury model where a segmental bone defect was combined with a peripheral nerve gap. Our results indicated that although tissue regeneration was not impaired, the composite injury group experienced a marked functional deficit in the operated limb compared to single-tissue injury. Second, we developed a model of composite bone and vascular extremity trauma by combining a critically-sized segmental bone defect with surgically-induced hind limb ischemia to evaluate the effects on BMP-2-mediated bone repair. Interestingly, our results demonstrated a stimulatory effect of the recovery response to ischemia on bone regeneration. Finally, we investigated early vascular growth and gene expression as potential mechanisms coupling the response to ischemia with bone defect repair. Although the response to ischemia promoted robust vascular growth in the thigh, it did not directly augment vascularization at the site of bone regeneration. In addition, the stimulatory effects of ischemia on bone regeneration could not be explained by gene expression alone based on the genes and time points investigated. Taken together, this thesis presents pioneering work on a new thrust of TE/RM research – tissue regeneration in models of composite injury. This work has provided new insights on the complexity of composite tissue repair, specifically in regard to the relationship between vascular tissue growth and bone healing. Going forward, successful leverage of models of composite tissue injuries will provide valuable test beds for screening new technologies, advance the understanding of tissue repair biology, and ultimately, may produce new therapeutic interventions for limb salvage and reconstruction that improve outcomes for extremity trauma patients.

This thesis presents a critical exploration of the ‘revitalization’ of Toronto’s Regent Park. Regent Park is Canada’s oldest and largest government subsidized housing development. Originally designed in 1947, Toronto City Council approved the revitalization of the neighbourhood in 2003. Within this thesis, Regent Park serves as a means to examine some of the ways in which urban planning and design, public policy, architecture and landscape architecture interact with people’s daily practices in their socioeconomic and cultural contexts, to ‘rebuild the social’. In order to do this, the thesis begins by presenting an account of the original development, providing a sociohistorical context for understanding the more recent revitalization. Secondly, the thesis provides a review of relevant theoretical literature pertaining to the idea that design shapes society, discussing key aspects of modernist and postmodernist accounts of the city, arguing for the salience of a broadly ‘relational’ model inspired by the work of Julier (2008) and others. Thirdly, the thesis conducts an empirical analysis of the recent revitalization process, using a mixed methodology of documentary analysis and in-depth interviews with a key developer and the residents of Regent’s park. This analysis explores the ideological commitments at play within the planning process, as well as the practice of planning itself, investigating how theories of design and planning relate to the actual process of planning, including the political and financial obligations. The analysis then compares the intentions of the design with the inhabitant’s lived experience within the space, focusing on the inhabitants’ active role in negotiating the space in ways that were ‘unplanned’. This thesis provides a sociological exploration of Regent Park as a complex site of interaction between the design of the space (influenced by theories of design, as well as economic, political and social motivations), the materials that make up that space, and the actual use of the space by residents, the outcomes of which challenge deterministic accounts of urban development. / Thesis (Master, Sociology) -- Queen's University, 2011-09-27 16:29:31.729

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