"July 1999." / Thesis (Ph.D.)--Chinese University of Hong Kong, 1999. / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Thesis (M. Phil.)--University of Hong Kong, 2006. / Title proper from title frame. Also available in printed format.

Thesis (Ph. D.)--University of Chicago, Dept. of Pathology, December 2001. / Includes bibliographical references. Also available on the Internet.

The human melanocortin receptors (hMCRs) play a fundamental role in human behavior such as satiety, feeding, sexual and more. A set of SHU9119 peptide derivatives were studied for their structure-activity relationships. These peptides contained a sequential a-N-methylation amino acid scan.A second set of peptide derivatives intended to be used to create TNF-a; inhibition, via the melanocortin receptors. These peptides were shown to bind to all of the hMCR receptors, and only exhibit cAMP stimulation at hMC1R/hMC5R.The data from both of the sets of compounds illustrate that small changes in the stereochemistry of the SH9119 and TNF-a; derivatives cause drastic changes in the binding and the agonistic/antagonist properties of the compounds.This thesis determined the effect that hMC1R mutations have on the binding and cAMP response of well characterized ligands. This study ruled out 9 different residues for being the required for the cAMP response of the hMC1R.

Due to its escalating prevalence, obesity is becoming a leading cause of morbidity and mortality worldwide. Obesity is a complex health problem accompanied by metabolic abnormalities and low-grade inflammation that increases the risk for developing comorbidities including type 2 diabetes. Recent evidence supports a role for fat (adipose) tissue derived factors, called adipokines, in the development of obesity and obesity-related metabolic pathologies. Chemerin is an adipokine that mediates immune and metabolic effects through the chemokine-like receptor 1 (CMKLR1). Chemerin is secreted as an inactive proform, prochemerin, which subsequently undergoes enzymatic cleavage into multiple chemerin products that differentially activate CMKLR1. Multiple studies have reported elevated total chemerin (a combination of prochemerin and various chemerin products) in obese humans suggesting chemerin involvement in obesity pathophysiology. However, the observational nature of these human studies have restricted them from identifying specific forms of chemerin that are elevated in obesity and the mechanisms that govern them. Herein, I have reported that the levels of both serum total chemerin and chemerin products capable of activating CMKLR1 are elevated in obese mice and in wild type mice following treatment with an obesity-associated inflammatory mediator tumor necrosis factor-? (TNF?). Likewise, cultured adipocytes produced active chemerin under basal conditions and highly active chemerin following TNF? treatment as measured by CMKLR1 activation. The current belief is that prochemerin circulates through blood primed for activation by immune and fibrinolytic enzymes present within injured tissues. My results challenge this theory, identifying adipocytes as cells alone produce and proteolytically activate chemerin. Under basal conditions, a balance between activating serine proteases and deactivating aminopeptidases governed the amount of CMKLR1-activating chemerin formed by adipocytes. Treatment of adipocytes with TNF? elevated the levels of serine proteases elastase and tryptase, which cumulatively shifted the proteolytic balance toward the production of chemerin products that highly activate CMKLR1. Taken together, my results are the first to identify that local TNF? triggers increased adipocyte production of chemerin providing an explanation for the elevated concentrations of chemerin in obese animals and humans. Furthermore, adipocyte processing represents a novel mechanism that likely governs the amount and type of circulating chemerin in obesity.

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Antigen induced activation of Th1 cells in the peripheral blood leads to elevated production of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) that have been directly linked to disease induction and neuropathic pain. It was hypothesized that following antigenic induction, cytokines gain access to the spinal cord and participate in direct cellular interaction with dorsal horn neurons. Using an animal model of MS, we show that TNF-α gene and protein expression in the dorsal root ganglia (DRG) and spinal cord tissue is increased in the active group. In addition, our findings show TNF-α mRNA expression in the dorsal root entry point. Therefore, our results support the hypothesis that antigen induced DRG derived TNF-α can transport to the spinal cord via the dorsal roots and is involved in the underlying pathogenesis of MS induced neuropathic pain.

Multiple Sclerosis (MS) is an autoimmune disease of the central nervous system (CNS). Antigen induced activation of Th1 cells in the peripheral blood leads to elevated production of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) that have been directly linked to disease induction and neuropathic pain. It was hypothesized that following antigenic induction, cytokines gain access to the spinal cord and participate in direct cellular interaction with dorsal horn neurons. Using an animal model of MS, we show that TNF-α gene and protein expression in the dorsal root ganglia (DRG) and spinal cord tissue is increased in the active group. In addition, our findings show TNF-α mRNA expression in the dorsal root entry point. Therefore, our results support the hypothesis that antigen induced DRG derived TNF-α can transport to the spinal cord via the dorsal roots and is involved in the underlying pathogenesis of MS induced neuropathic pain.

No description available.

Amendments inserted inside front cover. / Bibliograpghy: leaves 111-139. / xvi, 139, [29] leaves, [10] leaves of plates : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / The in vivo adminstration of Tumour Necrosis Factor-alpha as an antineoplastic agent has been severely restricted by dose-limiting side effects. Human TNF mutants with selective binding to the Human TNF receptors were employed to examine the role of these receptors in the mediation of TNF's cytotoxic and proinflammatory activities. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 1995?

Diss. (sammanfattning) Uppsala : Univ., 2003. / Härtill 6 uppsatser.