Meltwater reaching the base of the snowpack may either infiltrate the underlying stratum, run off, or refreeze, forming a basal ice layer. Frozen ground underneath a melting snowpack constrains infiltration promoting runoff and refreezing. Compositional changes in chemistry take place for each of these flowpaths as a result of phase change, contact between meltwater and soil, and mixing between meltwater and soil water. Meltwater ion concentrations and infiltration rate into frozen soils both decline rapidly as snowmelt progresses. Their temporal association is highly non-linear and the covariance must be compensated for in order to use time-averaged values to calculate chemical infiltration over a melt event. This temporal covariance is termed �enhanced infiltration� and represents the additional ion load that infiltrates due to the timing of high meltwater ion concentration and infiltration rate. Both theoretical and experimental assessments of the impact of enhanced infiltration showed that it causes a greater ion load to infiltrate leading to relative dilute runoff water. Sensitivity analysis showed that the magnitude of enhanced infiltration is governed by initial snow water equivalent, average melt rate, and meltwater ion concentration factor. Based on alterations in water chemistry due to various effects, including enhanced infiltration, three major flowpaths could be distinguished: overland flow, organic interflow, and mineral interflow. Laboratory experiments were carried out in a temperature-controlled environment to identify compositional changes in water from these flowpaths. Samples of meltwater, runoff, and interflow were filtered and analyzed for major anions and cations. Chemical signatures for each flowpath were determined by normalizing runoff and interflow concentrations using meltwater concentrations. Results showed that changes in ion concentrations were most significant for H+, NO3�, NH4+, Mg2+, and Ca2+. Repeated flushes of meltwater through each interflowpath caused a washout of ions. In the field, samples of soil water and ponding water were collected daily from a Rocky Mountain hillslope during snowmelt. Their normalized chemical compositions were compared to the laboratory-identified signatures to evaluate the flowpath. The majority of the flowpaths sampled had chemical signatures, which indicated mineral interflow, only 10% showed unmixed organic interflow.

Group A streptococcal disorders can result from autoantibodies generated against M proteins. These autoantibodies cross react with the basal ganglia resulting in movement disorders. Previously, we demonstrated binding of streptococcal mAb10F5, with CPu and phospholipids. To determine if mAb10F5 binding to basal ganglia and phospholipids is due to virulence of the antibody or antibody subtype, rats were injected with control IgG2 antibodies and euthanized after 24, 48, or 72 hours. Brains were harvested and immunofluorescence was used to analyze brain slices. Control IgG2 rats showed significantly less fluorescence in the CPu than mAb10F5 injected rats at every time point. These findings reaffirm 10F5 is an anti-basal ganglia antibody. To evaluate mechanism of antibody entry, mAb10F5 was examined for anti-phospholipid activity. MAb10F5 displayed greater affinity to phospholipids when compared to IgG2 controls. Our findings support mAb10F5 is an anti-basal ganglia and anti-phospholipid antibody due to its own virulence. / Access to thesis permanently restricted to Ball State community only / Department of Physiology and Health Science

This doctoral thesis examines how modernisation affects and is affected by existing local culture and identity. It is about the relation between the social and mental barriers experienced, expressed and manifested in the social culture of local community, and modernisation’s dynamic powers over time. The thesis deals with different time periods from the 1800’s until today with regard to expressions and consequences of modernity. People during the societal transformation of Sweden in the 19th and 20th centuries are culturally depicted from a micro-perspective. An overall perspective for the analysis of modernity uses the concepts of basal and variable modernity, borrowed from the historian of ideas Sven-Eric Liedman. The perspective makes possible the separation between on the one hand the structural modernisation within the fields of economy, technology and natural sciences, and on the other hand the cultural modernity manifested in conceptions of the world, politics, existential viewpoints, aesthetic expressions and social culture. Within the first-mentioned fields, where basal modernity dominates, a uniform and cumulative developmental pattern emerges as well as an almost self-propelled continuity toward the next innovation or stage of development. Within the latter fields, however, a non-uniform pattern emerges, where modernisation is constantly the object of alternative interpretations and attitudes. This variable modernity is characterised by a cultural struggle between conflicting ideologies and strategies in relation to ongoing modernisation. Different individuals and groups position themselves between acceptance and resistance, progressiveness and the critique of civilisation, the preservation of traditions and the will to change. In this course of events new affinities and identifications, but also new dissociations and antagonisms are created in local social contexts. Modernity leads both to the obliteration of boundaries and to the emergence of new social and mental boundaries. This process can also lead to existing geographical borders being charged with a new ideological content so their importance is revitalised.

The aim of this essay is to examine how people living in the Swedish countryside looked upon changes in the interiors through modernization in 1850-90. For the first time, there was an abundance of objects available in stores in the countryside that the majority of the population had money buy. Many novelties were introduced in the interior decoration of ordinary peoples´ homes. This study focuses on the introduction and use of wallpaper and is based on a questionnaire about wallpaper sent from the Nordiska museet, National museum of Culture history in Sweden, to people all over Sweden in 1948. 148 people responded to the questions about use and attitudes toward wallpaper during the second half of the 19th century. My theoretical perspective is cultural diffusion, the spread of cultural items, more specific the diffusion of innovations from larger to smaller places, often influenced by social elites, hierarchical diffusion, and between individuals, contagious diffusion. The analytical perspective used for the analysis is based on the concepts of basic and variable modernity, initiated by the historian Sven-Eric Liedman. Basic modernity describes the structural modernization in society as a whole within the fields of economy, technology and natural sciences. The variable modernity represents the different attitudes, likes and dislikes, opinions, viewpoints and cultural differences every individual possesses, the attitudes that decide how and if the modernity is received in each household. My intent has been to ascertain the factors that made production and distribution of relatively cheap wallpaper all over Sweden possible, pinpoint the most important driving forces for creating an interest in wallpaper within the villages, discover how wallpaper was introduced in the individual homes of farmers and how wallpaper was received. The use of wallpaper in the interiors has been examined in order to find out if, and how the modernization affected and was affected by the way people were living their lives within the home.

Sonic hedgehog (Shh) is a secreted morphogen involved in patterning a wide range of structures in the developing embryo. When cells receive the Shh signal a cascade of effects begin which in turn regulate downstream target genes. The genes controlled by Sonic hedgehog provide messages instructing cells how to differentiate or when to divide. Disruption of the hedgehog signalling cascade leads to a number of developmental disorders and plays a key role in the formation of a range of human cancers. Patched, the receptor for Shh, acts as a tumour suppressor and is mutated in naevoid basal cell carcinoma syndrome (NBCCS). NBCCS patients display a susceptibility to tumour formation, particularly for basal cell carcinoma (BCC). The discovery of Patched mutations in sporadic BCCs and other tumour types further highlights the importance of this pathway to human cancer. The identification of genes regulated by hedgehog is crucial for understanding how disruption of this pathway leads to neoplastic transformation. It is assumed that the abnormal expression of such genes plays a large role in directing cells to divide at inappropriate times. Only a small number of genes controlled by Shh have been described in vertebrate tissues. In the work presented in this thesis a Sonic hedgehog responsive embryonic mouse cell line, C3H/10T1/2, was used as a model system for hedgehog target gene discovery. Known downstream target genes were profiled to determine their induction kinetics, building up a body of knowledge on the response to Shh for this cell type. During this work, it was discovered that C3H/10T1/2 cells do not become fully competent to respond to Shh stimulation until the cells reach a critical density, a factor that had to be taken into account when determining timepoints of interest for further investigation. Several techniques were employed to identify genes that show expression changes between Shh stimulated and control cells. In one of these techniques, RNA from cell cultures activated with Shh was used to interrogate cDNA microarrays, and this provided many insights into the downstream transcriptional consequences of hedgehog stimulation. Microarrays consist of thousands of spots of DNA of known sequence gridded onto glass slides. Experiments using this technology allow the expression level of thousands of genes to be measured simultaneously. Independent stimulation methods combined with northern blotting were used to investigate individual genes of interest, allowing genuine targets to be confirmed and false positives eliminated. This resulted in the identification of eleven target genes. Seven of these are induced by Sonic hedgehog (Thrombomodulin (Thbd), Glucocorticoid induced leucine zipper (Gilz), Brain factor 2 (Bf2), Nuclear receptor subfamily 4, group A, member 1 (Nr4a1), Insulin-like growth factor 2 (Igf2), Peripheral myelin protein 22 (Pmp22), Lim and SH3 Protein 1 (Lasp1)), and four are repressed (Secreted frizzled related proteins 1 and 2 (Sfrp1 and Sfrp2), Macrophage inflammatory protein-1 gamma (Mip-1?), and Anti-mullerian hormone (Amh)). The majority of these represent novel downstream genes not previously reported as targets of Shh. The new target genes have a diverse range of functions, and include transcriptional regulators and molecules known to be involved in regulating cell growth or apoptosis. The corroboration of genes previously implicated in hedgehog signalling, along with the finding of novel targets, demonstrates both the validity and power of the C3H/10T1/2 system for Shh target gene discovery. The identification of novel Sonic hedgehog responsive genes provides candidates whose abnormal expression may be decisive in initiating tumour formation and future studies will investigate their role in development and disease. It is expected that such findings will provide vital clues to the aetiology of various human cancers, and that an understanding of their roles may ultimately provide greater opportunities in the future design of anti-tumour therapies.

Sonic hedgehog (Shh) is a secreted morphogen involved in patterning a wide range of structures in the developing embryo. When cells receive the Shh signal a cascade of effects begin which in turn regulate downstream target genes. The genes controlled by Sonic hedgehog provide messages instructing cells how to differentiate or when to divide. Disruption of the hedgehog signalling cascade leads to a number of developmental disorders and plays a key role in the formation of a range of human cancers. Patched, the receptor for Shh, acts as a tumour suppressor and is mutated in naevoid basal cell carcinoma syndrome (NBCCS). NBCCS patients display a susceptibility to tumour formation, particularly for basal cell carcinoma (BCC). The discovery of Patched mutations in sporadic BCCs and other tumour types further highlights the importance of this pathway to human cancer. The identification of genes regulated by hedgehog is crucial for understanding how disruption of this pathway leads to neoplastic transformation. It is assumed that the abnormal expression of such genes plays a large role in directing cells to divide at inappropriate times. Only a small number of genes controlled by Shh have been described in vertebrate tissues. In the work presented in this thesis a Sonic hedgehog responsive embryonic mouse cell line, C3H/10T1/2, was used as a model system for hedgehog target gene discovery. Known downstream target genes were profiled to determine their induction kinetics, building up a body of knowledge on the response to Shh for this cell type. During this work, it was discovered that C3H/10T1/2 cells do not become fully competent to respond to Shh stimulation until the cells reach a critical density, a factor that had to be taken into account when determining timepoints of interest for further investigation. Several techniques were employed to identify genes that show expression changes between Shh stimulated and control cells. In one of these techniques, RNA from cell cultures activated with Shh was used to interrogate cDNA microarrays, and this provided many insights into the downstream transcriptional consequences of hedgehog stimulation. Microarrays consist of thousands of spots of DNA of known sequence gridded onto glass slides. Experiments using this technology allow the expression level of thousands of genes to be measured simultaneously. Independent stimulation methods combined with northern blotting were used to investigate individual genes of interest, allowing genuine targets to be confirmed and false positives eliminated. This resulted in the identification of eleven target genes. Seven of these are induced by Sonic hedgehog (Thrombomodulin (Thbd), Glucocorticoid induced leucine zipper (Gilz), Brain factor 2 (Bf2), Nuclear receptor subfamily 4, group A, member 1 (Nr4a1), Insulin-like growth factor 2 (Igf2), Peripheral myelin protein 22 (Pmp22), Lim and SH3 Protein 1 (Lasp1)), and four are repressed (Secreted frizzled related proteins 1 and 2 (Sfrp1 and Sfrp2), Macrophage inflammatory protein-1 gamma (Mip-1?), and Anti-mullerian hormone (Amh)). The majority of these represent novel downstream genes not previously reported as targets of Shh. The new target genes have a diverse range of functions, and include transcriptional regulators and molecules known to be involved in regulating cell growth or apoptosis. The corroboration of genes previously implicated in hedgehog signalling, along with the finding of novel targets, demonstrates both the validity and power of the C3H/10T1/2 system for Shh target gene discovery. The identification of novel Sonic hedgehog responsive genes provides candidates whose abnormal expression may be decisive in initiating tumour formation and future studies will investigate their role in development and disease. It is expected that such findings will provide vital clues to the aetiology of various human cancers, and that an understanding of their roles may ultimately provide greater opportunities in the future design of anti-tumour therapies.

Doctor of Philosophy(PhD) / BCC is the commonest cancer in European-derived populations and Australia has the highest recorded incidence in the world, creating enormous individual and societal cost in management of this disease. The incidence of this cancer has been increasing internationally, with evidence of a 1 to 2% rise in incidence in Australia per year over the last two decades. The main four epidemiological risk factors for the development of BCC are ultraviolet radiation (UVR) exposure, increasing age, male sex, and inability to tan. The pattern and timing of UVR exposure is important to BCC risk, with childhood and intermittent UVR exposure both associated with an increased risk. The complex of inherited characteristics making up an individual’s ‘sun sensitivity’ is also important in determining BCC risk. Very little is known about population genetic susceptibility to BCC outside of the rare genodermatosis Gorlin syndrome. Mutations in the tumour suppressor gene patched (PTCH) are responsible for this BCC predisposition syndrome and the molecular pathway and target genes of this highly conserved pathway are well described. Derangments in this pathway occur in sporadic BCC development, and the PTCH gene is an obvious candidate to contribute to non-syndromic susceptibility to BCC. The melanocortin 1 receptor (MC1R) locus is known to be involved in pigmentary traits and the cutaneous response to UVR, and variants have been associated with skin cancer risk. Many other genes have been considered with respect to population BCC risk and include p53, HPV, GSTs, and HLAs. There is preliminary evidence for specific familial aggregation of BCC, but very little known about the causes. 56 individuals who developed BCC under the age of 40 in the year 2000 were recruited from the Skin and Cancer Foundation of Australia’s database. This represents the youngest 7 – 8% of Australians with BCC from a database that captures approximately 10% of Sydney’s BCCs. 212 of their first degree relatives were also recruited, including 89 parents and 123 siblings of these 56 probands. All subjects were interviewed with respect to their cancer history and all reports of cancer verified with histopathological reports where possible. The oldest unaffected sibling for each proband (where available) was designated as an intra-family control. All cases and control siblings filled out a questionnaire regarding their pigmentary and sun sensitivity factors and underwent a skin examination by a trained examiner. Peripheral blood was collected from these cases and controls for genotyping of PTCH. All the exons of PTCH for which mutations have been documented in Gorlin patients were amplified using PCR. PCR products were screened for mutations using dHPLC, and all detectable variants sequenced. Prevalence of BCC and SCC for the Australian population was estimated from incidence data using a novel statistical approach. Familial aggregation of BCC, SCC and MM occurred within the 56 families studied here. The majority of families with aggregation of skin cancer had a combination of SCC and BCC, however nearly one fifth of families in this study had aggregation of BCC to the exclusion of SCC or MM, suggesting that BCCspecific risk factors are also likely to be at work. Skin cancer risks for first-degree relatives of people with early onset BCC were calculated: sisters and mothers of people with early-onset BCC had a 2-fold increased risk of BCC; brothers had a 5-fold increased risk of BCC; and sisters and fathers of people with early-onset BCC had over four times the prevalence of SCC than that expected. For melanoma, the increased risk was significant for male relatives only, with a 10-fold increased risk for brothers of people with early-onset BCC and 3-fold for fathers. On skin examination of cases and controls, several phenotypic factors were significantly associated with BCC risk. These included increasing risk of BCC with having fair, easyburning skin (ie decreasing skin phototype), and with having signs of cumulative sun damage to the skin in the form of actinic keratoses. Signs reflecting the combination of pigmentary characteristics and sun exposure - in the form of arm freckling and solar lentigines - also gave subjects a significantly increased risk BCC. Constitutive red-green reflectance of the skin was associated with decreased risk of BCC, as measured by spectrophotometery. Other non-significant trends were seen that may become significant in larger studies including associations of BCC with propensity to burn, moderate tanning ability and an inability to tan. No convincing trend for risk of BCC was seen with the pigmentary variables of hair or eye colour, and a non-significant reduced risk of BCC was associated with increasing numbers of seborrhoeic keratoses. Twenty PTCH exons (exons 2, 3, 5 to 18, and 20 to 23) were screened, accounting for 97% of the coding regions with published mutations in PTCH. Nine of these 20 exons were found to harbour single nucleotide polymorphisms (SNPs), seen on dHPLC as variant melting curves and confirmed on direct sequencing. SNPs frequencies were not significantly different to published population frequencies, or to Australian general population frequencies where SNP database population data was unavailable. Assuming a Poisson distribution, and having observed no mutations in a sample of 56, we can be 97.5% confident that if there are any PTCH mutations contributing to early-onset BCC in the Australian population, then their prevalence is less than 5.1%. Overall, this study provides evidence that familial aggregation of BCC is occurring, that first-degree relatives are at increased risk of all three types of skin cancer, and that a combination of environmental and genetic risk factors are likely to be responsible. The PTCH gene is excluded as a major cause of this increased susceptibility to BCC in particular and skin cancer in general. The weaknesses of the study design are explored, the possible clinical relevance of the data is examined, and future directions for research into the genetics of basal cell carcinoma are discussed.

PhD / When modeling a system as complex as the brain, considerable simplifications are inevitable. The nature of these simplifications depends on the available experimental evidence, and the desired form of model predictions. A focus on the former often inspires models of networks of individual neurons, since properties of single cells are more easily measured than those of entire populations. However, if the goal is to describe the processes responsible for the electroencephalogram (EEG), such models can become unmanageable due to the large numbers of neurons involved. Mean-field models in which assemblies of neurons are represented by their average properties allow activity underlying the EEG to be captured in a tractable manner. The starting point of the results presented here is a recent physiologically-based mean-field model of the corticothalamic system, which includes populations of excitatory and inhibitory cortical neurons, and an excitatory population representing the thalamic relay nuclei, reciprocally connected with the cortex and the inhibitory thalamic reticular nucleus. The average firing rates of these populations depend nonlinearly on their membrane potentials, which are determined by afferent inputs after axonal propagation and dendritic and synaptic delays. It has been found that neuronal activity spreads in an approximately wavelike fashion across the cortex, which is modeled as a two-dimensional surface. On the basis of the literature, the EEG signal is assumed to be roughly proportional to the activity of cortical excitatory neurons, allowing physiological parameters to be extracted by inverse modeling of empirical EEG spectra. One objective of the present work is to characterize the statistical distributions of fitted model parameters in the healthy population. Variability of model parameters within and between individuals is assessed over time scales of minutes to more than a year, and compared with the variability of classical quantitative EEG (qEEG) parameters. These parameters are generally not normally distributed, and transformations toward the normal distribution are often used to facilitate statistical analysis. However, no single optimal transformation exists to render data distributions approximately normal. A uniformly applicable solution that not only yields data following the normal distribution as closely as possible, but also increases test-retest reliability, is described in Chapter 2. Specialized versions of this transformation have been known for some time in the statistical literature, but it has not previously found its way to the empirical sciences. Chapter 3 contains the study of intra-individual and inter-individual variability in model parameters, also providing a comparison of test-retest reliability with that of commonly used EEG spectral measures such as band powers and the frequency of the alpha peak. It is found that the combined model parameters provide a reliable characterization of an individual's EEG spectrum, where some parameters are more informative than others. Classical quantitative EEG measures are found to be somewhat more reproducible than model parameters. However, the latter have the advantage of providing direct connections with the underlying physiology. In addition, model parameters are complementary to classical measures in that they capture more information about spectral structure. Another conclusion from this work was that a few minutes of alert eyes-closed EEG already contain most of the individual variability likely to occur in this state on the scale of years. In Chapter 4, age trends in model parameters are investigated for a large sample of healthy subjects aged 6-86 years. Sex differences in parameter distributions and trends are considered in three age ranges, and related to the relevant literature. We also look at changes in inter-individual variance across age, and find that subjects are in many respects maximally different around adolescence. This study forms the basis for prospective comparisons with age trends in evoked response potentials (ERPs) and alpha peak morphology, besides providing a standard for the assessment of clinical data. It is the first study to report physiologically-based parameters for such a large sample of EEG data. The second main thrust of this work is toward incorporating the thalamocortical system and the basal ganglia in a unified framework. The basal ganglia are a group of gray matter structures reciprocally connected with the thalamus and cortex, both significantly influencing, and influenced by, their activity. Abnormalities in the basal ganglia are associated with various disorders, including schizophrenia, Huntington's disease, and Parkinson's disease. A model of the basal ganglia-thalamocortical system is presented in Chapter 5, and used to investigate changes in average firing rates often measured in parkinsonian patients and animal models of Parkinson's disease. Modeling results support the hypothesis that two pathways through the basal ganglia (the so-called direct and indirect pathways) are differentially affected by the dopamine depletion that is the hallmark of Parkinson's disease. However, alterations in other components of the system are also suggested by matching model predictions to experimental data. The dynamics of the model are explored in detail in Chapter 6. Electrophysiological aspects of Parkinson's disease include frequency reduction of the alpha peak, increased relative power at lower frequencies, and abnormal synchronized fluctuations in firing rates. It is shown that the same parameter variations that reproduce realistic changes in mean firing rates can also account for EEG frequency reduction by increasing the strength of the indirect pathway, which exerts an inhibitory effect on the cortex. Furthermore, even more strongly connected subcircuits in the indirect pathway can sustain limit cycle oscillations around 5 Hz, in accord with oscillations at this frequency often observed in tremulous patients. Additionally, oscillations around 20 Hz that are normally present in corticothalamic circuits can spread to the basal ganglia when both corticothalamic and indirect circuits have large gains. The model also accounts for changes in the responsiveness of the components of the basal ganglia-thalamocortical system, and increased synchronization upon dopamine depletion, which plausibly reflect the loss of specificity of neuronal signaling pathways in the parkinsonian basal ganglia. Thus, a parsimonious explanation is provided for many electrophysiological correlates of Parkinson's disease using a single set of parameter changes with respect to the healthy state. Overall, we conclude that mean-field models of brain electrophysiology possess a versatility that allows them to be usefully applied in a variety of scenarios. Such models allow information about underlying physiology to be extracted from the experimental EEG, complementing traditional measures that may be more statistically robust but do not provide a direct link with physiology. Furthermore, there is ample opportunity for future developments, extending the basic model to encompass different neuronal systems, connections, and mechanisms. The basal ganglia are an important addition, not only leading to unified explanations for many hitherto disparate phenomena, but also contributing to the validation of this form of modeling.

Sonic hedgehog (Shh) is a secreted morphogen involved in patterning a wide range of structures in the developing embryo. When cells receive the Shh signal a cascade of effects begin which in turn regulate downstream target genes. The genes controlled by Sonic hedgehog provide messages instructing cells how to differentiate or when to divide. Disruption of the hedgehog signalling cascade leads to a number of developmental disorders and plays a key role in the formation of a range of human cancers. Patched, the receptor for Shh, acts as a tumour suppressor and is mutated in naevoid basal cell carcinoma syndrome (NBCCS). NBCCS patients display a susceptibility to tumour formation, particularly for basal cell carcinoma (BCC). The discovery of Patched mutations in sporadic BCCs and other tumour types further highlights the importance of this pathway to human cancer. The identification of genes regulated by hedgehog is crucial for understanding how disruption of this pathway leads to neoplastic transformation. It is assumed that the abnormal expression of such genes plays a large role in directing cells to divide at inappropriate times. Only a small number of genes controlled by Shh have been described in vertebrate tissues. In the work presented in this thesis a Sonic hedgehog responsive embryonic mouse cell line, C3H/10T1/2, was used as a model system for hedgehog target gene discovery. Known downstream target genes were profiled to determine their induction kinetics, building up a body of knowledge on the response to Shh for this cell type. During this work, it was discovered that C3H/10T1/2 cells do not become fully competent to respond to Shh stimulation until the cells reach a critical density, a factor that had to be taken into account when determining timepoints of interest for further investigation. Several techniques were employed to identify genes that show expression changes between Shh stimulated and control cells. In one of these techniques, RNA from cell cultures activated with Shh was used to interrogate cDNA microarrays, and this provided many insights into the downstream transcriptional consequences of hedgehog stimulation. Microarrays consist of thousands of spots of DNA of known sequence gridded onto glass slides. Experiments using this technology allow the expression level of thousands of genes to be measured simultaneously. Independent stimulation methods combined with northern blotting were used to investigate individual genes of interest, allowing genuine targets to be confirmed and false positives eliminated. This resulted in the identification of eleven target genes. Seven of these are induced by Sonic hedgehog (Thrombomodulin (Thbd), Glucocorticoid induced leucine zipper (Gilz), Brain factor 2 (Bf2), Nuclear receptor subfamily 4, group A, member 1 (Nr4a1), Insulin-like growth factor 2 (Igf2), Peripheral myelin protein 22 (Pmp22), Lim and SH3 Protein 1 (Lasp1)), and four are repressed (Secreted frizzled related proteins 1 and 2 (Sfrp1 and Sfrp2), Macrophage inflammatory protein-1 gamma (Mip-1?), and Anti-mullerian hormone (Amh)). The majority of these represent novel downstream genes not previously reported as targets of Shh. The new target genes have a diverse range of functions, and include transcriptional regulators and molecules known to be involved in regulating cell growth or apoptosis. The corroboration of genes previously implicated in hedgehog signalling, along with the finding of novel targets, demonstrates both the validity and power of the C3H/10T1/2 system for Shh target gene discovery. The identification of novel Sonic hedgehog responsive genes provides candidates whose abnormal expression may be decisive in initiating tumour formation and future studies will investigate their role in development and disease. It is expected that such findings will provide vital clues to the aetiology of various human cancers, and that an understanding of their roles may ultimately provide greater opportunities in the future design of anti-tumour therapies.

Diss. (sammanfattning) Linköping : Univ., 2004. / Härtill 5 uppsatser.