Thesis (Ph. D.)--University of Chicago, Dept. of Pathology, June 2002. / Includes bibliographical references. Also available on the Internet.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1969. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1968. / Typescript. Vita. eContent provider-neutral record in process. Description based on print version record. Includes bibliography.

Thèse (M.Sc.)--Université Laval, 2001. / Titre de la microfiche: Cloning and characterization of two forms of type 7 17 beta-... Bibliogr.: f. 72-85. Publié aussi en version électronique.

Thesis (Ph. D.)--Illinois State University, 2000. / Title from title page screen, viewed May 11, 2006. Dissertation Committee: David Borst (chair), Anthony Otsuka, Radheshyam Jayaswal, Paul Garris, David Williams. Includes bibliographical references (leaves 130-135) and abstract. Also available in print.

Thesis (Ph. D.)--Drexel University, 2007. / Includes abstract and vita. Includes bibliographical references (leaves 103-110).

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A recently discovered peptide hormone, pituitary adenylate cyclase-activating polypeptide (PACAP) regulates several endocrine systems affecting essential physiological processes such as metabolism, growth, reproduction, and the stress response. PACAP acts as a hypophysiotropic factor, is a potent secretogogue of insulin, regulates production and release of catecholamines from the adrenal medulla and acts as a neuromodulator in the sympathetic and parasympathetic nervous system. The primary structure of PACAP has been highly conserved during the evolution of chordates suggesting it plays an important physiological role. The objective of my thesis was to identify PACAP’s primary physiological function and to determine if it is essential for survival by generating a mouse line deficient in PACAP through targeted disruption of the PACAP gene locus. Postnatal PACAP expression was examined to determine sites of peripheral PACAP production. In addition, several splice variants of the PACAP gene with alternate 5’untranslated regions were identified suggesting a complex system for regulating expression of the mouse PACAP gene. A targeting vector that allows tissue specific or developmental stage specific knockout of the PACAP gene was constructed in the event that PACAP gene deletion resulted in embryonic lethality. PACAP null mice were generated from homologously recombined embryonic stem cells. Initial characterization of the PACAP null mice determined that in the absence of PACAP, mice died within the first two postnatal weeks with abnormal lipid metabolism. Lipid accumulation was present in liver, heart and skeletal muscle and serum lipids were high. Mitochondrial dysfunction in the liver was not the cause of the lipid accumulation, as P-oxidative function was normal. I conclude that PACAP null mice are unable to regulate lipid release from white adipose tissue stores, resulting in a flood of lipids to non-adipose tissues. The abnormal distribution of lipids observed in the PACAP null mice is characteristic of diabetes type 2, yet classical insulin resistance is not observed. Thus, elevated insulin levels were accompanied by low blood glucose levels and the response to a glucose challenge was normal. The uncontrolled release of free fatty acids may result if glucose that is taken up by cells can not be utilized and an alternate energy source is required or if white adipocytes only are insulin resistant. The PACAP null mice were temperature sensitive, in that when raised at 21“C they exhibited metabolic dysfunction and died by two weeks of age. At 24°C most (85%) of the mice survived to adulthood with no obvious signs of metabolic dysfunction. We have determined that the inability of the PACAP null pups to thermoregulate normally when exposed to a lower environmental temperature may be associated with decreased norepinephrine levels to the brown adipose tissue. PACAP may be important for the production and release of catecholamines in the adrenal gland or within the sympathetic nervous system in times of prolonged stress. A mechanistic connection between the lipid abnormalities and the temperature sensitivity in the PACAP null pups has yet to be made. Catecholamines affect a wide range of tissues and the problems associated with insulin regulation within the PACAP null mice may be due to the imbalance in catecholamine production. As one of two main stress response systems, the sympathetic nervous system elicits a vital coping mechanism in times of stress and PACAP’s ability to regulate this system may explain why the primary structure of PACAP has remained so highly conserved. PACAP is a wide acting hormone and therefore the metabolic problems seen in the PACAP null mice may result from altered regulation of several endocrine systems at once. Targeted disruption of the PACAP gene in mouse has revealed a role for PACAP in the regulation of lipid metabolism and in the sympathetic control of thermoregulation. / Graduate

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