Patients with trisomy of chromosome 21, known as Down’s syndrome (DS), have a lower incidence of solid tumours than unaffected age-matched individuals. However, the cellular and molecular basis for this observation is not well understood. We hypothesised that a direct link between Down’s syndrome and angiogenesis exists, whereby the overexpression of human chromosome 21 (Hsa21) genes causes the repression of angiogenesis (gene dosage effects) resulting in the inhibition of solid tumour growth. In this project we investigated the angiogenic phenotype of an animal model of Down’s syndrome, the Tc1 mouse, which contains a large freely segregating fragment of Hsa21 containing over 200 human genes. We found that the growth of both B16F0 melanoma and Lewis Lung Carcinoma cells was impaired in Tc1 mice. Tumour vascularity also was reduced. This is supportive of the epidemiological data from the human DS population and supports the hypothesis that Hsa21 contains anti-angiogenic genes. Candidate genes were selected due to their endothelial specificity or likelihood to function in angiogenesis based on functional data or similarity to other proteins. Ex vivo RNAi assays were used to examine their roles in angiogenesis. We have found that reducing the expression of human Adamts1, Erg, Jamb or Pttg1ip in Tc1 tissue can restore its angiogenic potential, suggesting that the dosage of these genes (i.e. 3 copies instead of 2) can inhibit angiogenesis. Following from this study we also examined the role of selected adhesion related genes found on chromosome 21 in angiogenesis. Cldn14 encodes the tight junction molecule Claudin14 but its role in angiogenesis was unknown. We found that partial, but not complete, depletion of Cldn14 can increase the proportion of non-lumenated tumour blood vessels; decrease supporting cell association with tumour vessels; and increase endothelial cell proliferation in vivo, ex vivo and in vitro. Taken together this series of experiments has identified novel regulators of angiogenesis and has demonstrated the gene dosage effects of a subset of Hsa21 genes on angiogenic processes.

Down's syndrome (DS) is a congenital disorder caused by trisomy of chromosome 21, giving rise to symptoms including intellectual disability, poor muscle tone and characteristic facial features. Located on chromosome 21 is a gene encoding ubiquitin specific protease 25 (USP25), a member of the deubiquitinating family of enzymes. Studies of partial trisomies have revealed that although the USP25 gene is situated outside the critical region of chromosome 21 required to be triplicated to induce full DS symptoms, it is in a region linked to mild mental retardation and muscle hypotonia. Previous data has shown that, when overexpressed, USP25 forms novel rod shaped structures approximately 3-5 μm in length and 0.3-0.6 μm wide, and with a copy number, on average, of no more than 1-2 per cell. These structures do not associate with any known cellular organelle or with any component of the cytoskeleton. In this work, endogenous USP25 rods were detected in cultures of primary human foetal astrocytes, and a comparison of healthy and DS human primary foetal astrocytes revealed that in the DS culture a higher percentage of astrocytes contain rods. The domains of USP25 required for rod formation were identified using a series of GFP-tagged deletion constructs. USP25 rods could be purified from HEK293 cells using subcellular fractionation techniques and were assayed for deubiquitinating activity; however, none was detected suggesting that rods may be catalytically inactive. Interacting partners of USP25 were identified using mass spectrometry, but none were found to localise in rods. Additionally, a USP25 null human embryonic stem cell line was generated in order to interrogate the function of USP25 in astrocytes, and was found to be deficient in maintaining the integrity of an epithelial cell layer in an in vitro model of the blood brain barrier.

No description available.

A forced choice reaction time (RT) task was used to assess developmental changes in filtering and the related ability to narrow the focus of the attentional lens among persons with autism as compared to a group of typically developing children matched on different standardized measures. The participants included 35 persons with autism (CAs between 8.3 and 13.2 years, M = 9.8 years) and 35 typically developing children (CAs between 4.8 and 7.3 years, M = 5.9 years) between the mental ages (MA) of 5 and 8 years. The measures used for matching include the Leiter International Performance Scale - Revised (Leiter-R; Roid and Miller, 1997), the Peabody Picture Vocabulary Test - Third Edition (PPVT-III; Dunn and Dunn, 1997), and the Expressive One Word Vocabulary Test (EOWVT; Gardner, 1990). The conditions varied with regard to the presence or absence of distractors, their proximity (none, close, and far) to a target stimulus, and the presence or absence of a visual window within which the target stimulus was presented. (Abstract shortened by UMI.)

No description available.

Thesis (Ph. D.)--Oregon State University, 2008. / Includes bibliographical references (leaves 93-94).

Thesis (M.S.)--Oregon State University, 2010. / Printout. Includes bibliographical references. Also available on the World Wide Web.

Thesis (Ph. D.)--Wisconsin. / Vita. Includes bibliographical references (leaves 276-292).

Thesis (D.Ed.Psych.) - University of Queensland, 2005. / Includes bibliography.

Thesis (Ph. D.)--Oregon State University, 2008. / Printout. Includes bibliographical references. Also available on the World Wide Web.