The role of glucocorticoid-induced tumour necrosis factor receptor in developing mouse sympathetic neurons

Hereditary sensory autonomic neuropathy IV (HSAN IV) is an autosomal recessive disorder characterised by inability to feel pain and anhidrosis and is a consequence of defective NGF/TrkA signalling and growth of sensory and sympathetic neurons. Glucocortiocoid-induced tumour necrosis factors receptor (GITR), a transmembrane protein, activated by its specific ligand, GITRL, is well known for its role in the regulation of innate and acquired immune system responses. Recently, GITR was found to be required for NGF-dependant and extracellular signal-related kinase 1/2 (ERK1/2)-induced neurite growth and target innervation in the developing sympathetic nervous system (SNS). Given this novel role of GITR, it is possible that strategies targeting GITR have potential therapeutic benefit in promoting neurite growth in autonomic neuropathies such as HSAN IV. Using P1 mouse SCG neurons as a model, in addition to various SCG cell treatments, knock down models and transfection methods, we investigated whether GITR increases the sensitivity of sympathetic neurons to NGF; the region of GITR required for the enhancement of NGF-promoted growth, the signalling pathways downstream of GITR and how extensively GITR is involved in regulating peripheral innervation of the SNS. Results indicate that the region responsible for the growth promoting effects of GITR lies in its juxtamembrane intracellular region (here termed the growth promoting domain (GPD)) of GITR. The GPD of GITR activates ERK1/2 and inhibits nuclear factor kappa B (NF-κB) in an inverse fashion to provide an optimal cellular growth environment for P1 SCG neurons. While deleting the GPD of GITR had no effect on TrkA expression, constitutive phosphorylation of specific sites in the GPD reduced TrkA expression indicating a possible role for GITR in increasing the sensitivity of SCG neurons to NGF by the regulation of these sites, TrkA expression and subsequent NGF/TrkA binding. GITR appears to be heterogeneously required for NGF-promoted target innervation of SCG neurons in some organs, implying additional factors are involved in extensive NGF-target innervation of the SNS. In conclusion, this study answers basic biological questions regarding the molecular mechanism behind the role of GITR in the development of the SNS, and provides a basis for future research if GITR modulation is to be developed as a strategy for promoting axonal growth.

Scientism and instrumentalism After the Bomb: Dr Strangelove, End Zone, Crash and The Wire

This thesis argues that through the prism of America’s Cold War, scientism has emerged as the metanarrative of the postnuclear age. The advent of the bomb brought about a new primacy for mechanical and hyperrational thinking in the corridors of power not just in terms of managing the bomb itself but diffusing this ideology throughout the culture in social sciences, economics and other such institutional systems. The human need to mitigate or ameliorate against the chaos of the universe lies at the heart of not just religious faith but in the desire for perfect control. Thus there has been a transference of power from religious faith to the apparent material power of science and technology and the terra firma these supposedly objective means supply. The Cold War, however was a highly ideologically charged opposition between the two superpowers, and the scientific methodology that sprang forth to manage the Cold War and the bomb, in the United States, was not an objective scientific system divorced from the paranoia and dogma but a system that assumed a radically fundamentalist idea of capitalism. This is apparent in the widespread diffusion of game theory throughout Western postindustrial institutions. The inquiry of the thesis thus examines the texts that engage and criticise American Cold War methodology, beginning with the nuclear moment, so to speak, and Dr Strangelove’s incisive satire of moral abdication to machine processes. Moving on chronologically, the thesis examines the diffusion of particular kinds of masculinity and sexuality in postnuclear culture in Crash and End Zone and finishing up its analysis with the ethnographic portrayal of a modern American city in The Wire. More than anything else, the thesis wishes to reveal to what extent this technocratic consciousness puts pressure on language and on binding narratives.