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Thesis advisor: Thomas N. Seyfried / Thesis advisor: Charles Hoffman / Bis(monoacylglycero)phosphate, BMP, is a negatively charged glycerol-phospholipid with an unusual sn-1;sn-1’ structural configuration. BMP is primarily enriched in endosomal/lysosomal membranes. BMP is thought to play a role in glycosphingolipid degradation and cholesterol transport. It constitutes only about 1-2% of the total phospholipids in most mammalian cells, but is abundant in lung alveolar macrophages where it can comprise up to 16% of the total phospholipids. BMP also accumulates in tissues of humans and animals with lysosomal storage disorders. However, little information is available on BMP levels in gangliosidosis brain tissue. In this work, I found that total BMP content was significantly greater in cells of macrophage/microglial origin than in cells of macroglial origin (astrocyte, oligodendrocyte progenitor), whether normal or tumorigenic. I also observed that BMP in brain was significantly greater in humans and in animals (mice, cats, American black bears) with either GM1 or GM2 ganglioside storage diseases, than in brains of normal subjects. Since BMP is associated with macrophages, I also analyzed the BMP levels in relation to disease-associated inflammation in gangliosidoses. I found that BMP levels were increased due to accumulation of primary storage material gangliosides, rather than an outcome of disease-associated inflammation. In addition, in this thesis I also explored the effect of new ketogenic diet formula from Solace Nutrition (KetoGen) on the growth and metastatic spread of the VM-M3 tumor. Most current drug therapies for cancer are toxic and only marginally effective in providing long-term management. Respiratory insufficiency with compensatory aerobic fermentation (Warburg effect) is the hallmark biochemical phenotype of nearly all neoplastic cells within tumors. Calorie restriction, which lowers blood glucose and elevates ketone bodies, is known to reduce tumor growth to a certain extent, however it does not reduce systemic metastasis. Tumor bearing VM mice were fed either a standard lab chow diet in unrestricted amounts (SD-UR), a standard lab chow restricted to obtain an 18% reduction in body weight (SD-R), or the KetoGen diet restricted (KG-R) to match the body weights of the SD-R group. Tumor size was significantly smaller and organ metastasis was significantly less in the KG-R group than in the SD-UR or SD-R groups. Even though blood glucose was reduced similarly in both the SD-R and KG-R groups, blood ketones were 3-fold higher in the KG-R group than in the SD-R group. These results show that VM-M3 tumor growth and systemic metastasis were managed better with the restricted KetoGen KD than with calorie restriction of a high carbohydrate standard diet. As all human and mouse tumors cells suffer from respiratory insufficiency, my findings suggest that the restricted KetoGen diet should be an effective non-toxic therapy against tumor growth and systemic metastatic cancer. / Thesis (PhD) — Boston College, 2015. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Biology.

The condition at settlement of the western rock lobster pueruli presumably reflects both their energetic condition in reaching the near shore and subsequent recruitment into adult populations. In recruiting to the near shore the pueruli swim across the continental shelf where oceanographic conditions are complex and likely influence the success of recruitment. The results from the biochemical studies are interpreted in light of the oceanography off the coast of Western Australia. I investigated the nutritional condition of larval phyllosomata, post-larval puerulus and first instar post-pueruli juveniles of the spiny lobster, Panulirus cygnus, to determine energy use during the non-feeding transitional puerulus stage. Biochemical analyses of lipid, fatty acid (FA) and protein revealed that lipid, in particular phospholipids, is primarily used for energy during the nonfeeding puerulus stage. Monounsaturated FA showed the greatest decline with development, whereas the polyunsaturated FA showed a high degree of sparing, suggesting these FA are not used as a substrate for energy production. The knowledge gained on the biochemistry of energy use in P. cygnus was then used to investigate the spatial and temporal variability in the nutritional condition, in particular lipid condition, of puerulus collected at three near shore locations (Alkimos, Jurien Bay and Dongara) along the Western Australia coast, and one offshore location (Houtman Abrolhos Islands). The one offshore location was chosen as I hypothesised that arriving pueruli are likely to be in a better state of nutrition than those arriving at more coastal locations where the potential journey from offshore larval feeding grounds to the near shore is considerably greater. This element of my research showed lipid levels to be inversely related, generally, to shelf width but were variable, suggesting pueruli may travel complex trajectories to reach nearshore settlement. The lipid and FA composition of pueruli was also consistent with spatial and seasonal variation in Leeuwin Current and coastal productivity regimes.