Diss. (sammanfattning) Göteborg : Göteborgs universitet, 2009. / Härtill 4 uppsatser.

Thesis (M.S.)--West Virginia University, 2002. / Title from document title page. Document formatted into pages; contains xi, 157 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 135-148).

IKK[alpha] is a 85KD serine/threonine protein kinase and a subunit of the IKK complex, which contains IKK[alpha], IKK[beta], and IKK[gamma]. IKK[alpha] and IKK[beta] are highly conserved and they contain three functional domains of kinase domain, leucine zipper (LZ), and helix-loop-helix (HLH). Although IKK[alpha] and IKK[beta] can phosphorylate IκB proteins in vitro, IKK[alpha] and IKK[beta] have distinct physiological functions during mouse development. Genetic studies showed that IKK[alpha] is essential for embryonic skin development in mice. Mice deficient in IKK[alpha] display a hyperplastic epidermis that lacks terminal differentiation, resulting a death soon after birth because of the severely impaired skin. Recently, we reported a reduction in IKK[alpha] expression and identified somatic Ikk[alpha] mutations in a high proportion of poorly differentiated human squamous cell carcinomas (SCCs) (Liu et al., 2006). The aim of this study is to investigate the novel role of IKK[alpha] in skin carcinogenesis. We firstly examined IKK[alpha] expression and Ikk[alpha] mutations in human SCCs and found a reduction of IKK[alpha] in poorly differentiated human SCCs and identified somatic Ikk[alpha] mutations in exon 15 of Ikk[alpha] in human SCCs. We then examined the susceptibility of Ikk[alpha] hemizygotes to chemical carcinogeninduced skin carcinogenesis. In this chemical carcinogen-induced skin carcinogenesis setting, 7,12-dimethylbenz[a]anthracene (DMBA) induces Ras mutations and 12-Otetradecanoyl-phorbol-13-acetate (TPA) promotes Ras-initiated cell proliferation. We found two times more papillomas and eleven times more carcinomas in Ikk[alpha superscript +/-] mice than in Ikk [alpha] superscript +/+] mice induced by DMBA/TPA. Ikk[alpha superscript +/-] mice developed larger and earlier tumors than did Ikk[alpha superscript +/+] mice. Poorly differentiated carcinomas expressed low levels of IKK[alpha]. Ninety five percent of the Ikk[alpha superscript +/-] carcinomas and 44% of the Ikk[alpha superscript +/-] papillomas lost the remaining wild type Ikk[alpha] allele. This result indicates that the remaining one wild type Ikk[alpha] allele is important for preventing malignant carcinoma conversion. Also Ikk[alpha] mutations were detected in these skin tumors. Reduced IKK[alpha] was found to enhance TPA-induced mitogenic and angiogenic activities in mouse skin. Taken together, these results suggest that reduction of IKK[alpha] expression provides a selective growth advantage, which cooperates with DMBA-initiated Ras activity to promote skin carcinogenesis. In addition, we observed a small group of FVB female Ikk [alpha superscript +/-] mice for 1.5 years and found that 12/ 24 mice developed various spontaneous tumors including mammary gland carcinomas, uterine and ovary tumors, and dermal fibrosacomas. Somatic Ikk[alpha] mutations, elevated IKK/ NF[subscript -k]B and extracellular signal-regulated kinases (ERK) activities and elevated cyclin D1 levels were detected in these spontaneous tumors. These results suggest that these molecular alterations may contribute to the development of these tumors although the precise role of the down-regulation of IKK in the development of the tumors remains to be determined. Overall, our data and other published results suggest that IKK[alpha] is a new tumor suppressor in men and mice. / text

Prostaglandin E₂ (PGE₂), the most abundant prostaglandin in mouse skin, has been shown to promote skin tumor development. EP1 is one of four PGE₂ receptors. EP1 mRNA levels analyzed by a quantitative real-time polymerase chain reaction were increased after treatments of 12-O-tetradecanoylphorbol 13-acetate (TPA) or ultraviolet light on skin as well as in 7,12 dimethylbenz[a]anthracene (DMBA)/TPA or UV-induced skin tumors. To determine whether the EP1 receptor levels affect skin tumor development, we generated BK5.EP1 transgenic mice which overexpress EP1 in the basal layer of the epidermis. The skins of these mice are histologically indistinguishable from wild type mice. To determine the role of EP1 in skin tumor development, a DMBA/TPA skin carcinogenesis protocol was used. EP1 transgenic mice had a reduced tumor multiplicity and a reduced tumor incidence compared to wild type mice, but had a higher papilloma to carcinoma conversion rate. In a DMBA-only skin carcinogenesis protocol, EP1 transgenic mice developed more tumors than wild type mice. The effect of EP1 on cell proliferation was measured in vivo. After TPA treatment, cell proliferation was induced in both EP1 transgenic mice and wild type mice to a similar extent. However, 5 days after DMBA treatment, there were about 2-fold more proliferating cells in the basal layer of the epidermis of EP1 transgenic mouse skin than in wild type mice. To confirm that the enhanced tumor formation in transgenic mice is in fact PGE₂ dependent, EP1 transgenic mice were administered the selective cyclooxygenase-2 inhibitor Celecoxib or a control diet starting 1 week before DMBA treatment. Surprisingly, there was no lesion development on mice that were fed Celecoxib. Histological sections of skin from Celecoxib-fed mice showed a fairly normal skin histology 2 weeks after DMBA treatment compared to the pronounced pseudocarcinomatous hyperplasia observed in control diet mice. Therefore, it can be concluded that EP1 signaling increases PGE₂ production through COX-2 induction and promotes tumor development. / text

The skin conductance response is involved in the preparation for and response to stimuli with emotional significance. The neural mechanisms responsible for the generation of the skin conductance response are not well understood despite the common use of this signal as an index of emotional response. Data from anatomical, lesion, and neuroimaging studies in humans suggest that the amygdala, a component of the brain circuit for emotion, plays a critical role in the generation of the skin conductance response. Here we employ a novel combination of existing techniques to understand the stimuli that elicit skin conductance responses in the monkey and the neural mechanisms in the amygdala that participate in its generation. We recorded skin conductance responses in monkeys trained to perform a passive image viewing task. This paradigm is a staple of human emotion research but to date has not been adapted to the monkey. In addition, skin conductance responses to these stimuli were recorded in conjunction with single unit responses from the amygdala. This study addresses the relationship between the activity of single neurons recorded from identified nuclei of the monkey amygdala and autonomic responses. Neurons in multiple nuclei of the amygdala showed reliable changes in neuronal discharge prior to the skin conductance response. These neurons were primarily in the dorsal nuclei of the amygdala, which confirms predictions made from anatomical and neuroimaging data. It is suggested that these changes in neuronal discharge may correspond to the generation of this autonomic component of the expression of emotion.

Thesis (M.S.)--University of Alabama at Birmingham, 2007. / Additional advisors: Dale S. Feldman, Mary J. MacDougall, Laura Timares. Description based on contents viewed Feb. 4, 2008; title from title screen. Includes bibliographical references (p. 39-40).

Diss. (sammanfattning) Linköping : Univ., 2003. / Härtill 5 uppsatser.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 5 uppsatser.

Thesis (Ph.D.)--Edith Cowan University, 2006. / Submitted to the Faculty of Computing, Health and Science. Includes bibliographical references.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2007. / Härtill 4 uppsatser.