The aged T cell is characterized by decreased responsiveness to stimulation. Aging is associated with reduced membrane glycerophospholipid (GPL) to cholesterol ratios so it is interesting that deletion of mitochondrial glycerol-3-phosphate acyltransferase-1 which catalyzes the first step in de novo GPL synthesis induces an aged T cell phenotype in otherwise healthy mice. GPAT-1 could regulate T cell function through three possible mechanisms: maintenance of membrane GPL ratios and membrane based signaling, providing a specific substrate for downstream signaling, or direct regulation of cellular metabolism. Therefore, the goal of this project was to determine whether these mechanisms contribute to the dysfunctional T cell phenotype observed with decreased GPAT-1 activity. T cell stimulation requires significant upregulation of metabolic processes to drive clonal expansion and cytokine production. T cell dysfunction in GPAT-1 knockout mice may be partially explained by altered metabolic function. We found that GPAT-1 KO T cells have significantly reduced basal respiration rates and spare respiratory capacity which is not compensated for by increased glycolytic metabolism suggesting an inherent metabolic defect in GPAT-1 KO T cells. To better understand mechanistically how GPAT-1 regulates T cell function we moved into the Jurkat T cell line and found that shRNA mediated knockdown of the human isoform of GPAT-1 (GPAM) recapitulated key aspects of the dysfunctional T cell phenotype we observed in the mouse including highly significant reductions in IL-2 production and altered membrane GPL to cholesterol ratios. Phosphatidic acid addition was not capable of rescuing these deficiencies suggesting that GPAT-1/GPAM activity is required for proper T cell function. This was the first time that GPAT-1 activity has been shown to be important for T cell function in a non-murine model system and strongly suggests that GPAT-1/GPAM deficiency regulates T cell function at the cellular level. We further demonstrate that phosphorylation of ZAP-70 a proximal effector of T cell activation is significantly reduced in GPAM knock down Jurkat T cells, suggesting that membrane based signaling is dysfunctional. Taken together these data suggest that GPAT-1 is necessary for regulating cellular energy demands in T cells and essential for optimal T cell activation following stimulation. / text

published_or_final_version / Paediatrics and Adolescent Medicine / Doctoral / Doctor of Philosophy

The Aegean region contains numerous metamorphic core complexes that reflect post-collision extensional tectonics. The largest of these is the Menderes Massif of western Turkey, which covers an area of ~40,000 km². The Selimiye Shear Zone bounds its southern border and is a key location for studying the metamorphic history of the massif. Models of the tectonic evolution of the region requires an understanding of the peak pressure-temperature (P-T) conditions recorded by rocks in the massif, and the time (t) at which they achieved those conditions. However, limited P-T-t data exists in the Southern Menderes Massif. Here, P-T-t data was obtained from garnet-bearing rocks collected perpendicular to strike along seven transects spaced about 35 km across the Selimiye Shear Zone. Garnets in nine samples from four transects were analyzed using high-resolution back-scattered electron (BSE) imagery, X-ray element (Fe, Mg, Mn, Ca and Y) maps, and quantitative compositional analyses. Both zircon and monazite grains were dated in rock thin section using Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) and Secondary Ion Mass Spectrometry (SIMS) to ascertain the timing of events recorded by the rocks. Some garnet X-ray element maps show zoning consistent with multiple stages of growth, diffusion, and retrogression. Distinct zones in each sample are visible on high contrast BSE images and can be related to Y, Fe, and Mn contents. The conventional garnet + biotite geothermometer and garnet + plagioclase + muscovite + biotite geobarometer were used to estimate peak metamorphic P-T conditions. These range from 556±10°C to 671±27°C, and 15.3±0.2 kbar to 22.4±0.5 kbar. The temperatures are similar to previous estimates, but the pressures appear about ~10 kbar higher the previous estimates. U-Pb zircon ages range from 2022±30 Ma (13.4% disc.) to 254±5 Ma (13.4% disc.). Based on Th/U contents, the oldest ages are likely related to inherited grains from magmatic sources. The youngest zircon age is the first reported Triassic grain from the Southern Menderes Massif and may relate to the closure event of the Paleo-Tethyan Ocean. A younger history is recorded by U-Pb and Th-Pb monazite ages, which range Cretaceous to Miocene. Monazite geochronology is hindered by the contamination of high amounts of common Pb, but U-Pb and Th-Pb age calculations show Miocene to Jurassic ages. The textures of monazite (i.e. drusy, filling cracks of garnet and in reaction with allanite) imply that ages could record crystallization and/or fluid dissolution/reprecipitation mediated events in the Oligocene. Data reported here support the observation that polymetamorphic events are recorded in the Southern Menderes Massif rocks in close proximity to the Selimiye Shear Zone. Two options are possible environments of continental exhumation of rocks along the zone: (1) a polymetamorphic history that records relict high-pressures from previous metamorphic events or (2) a single-stage exhumation of high-pressure rocks. / text

The Aegean region contains numerous metamorphic core complexes that reflect post-collision extensional tectonics. The largest of these is the Menderes Massif of western Turkey, which covers an area of ~40,000 km². The Selimiye Shear Zone bounds its southern border and is a key location for studying the metamorphic history of the massif. Models of the tectonic evolution of the region requires an understanding of the peak pressure-temperature (P-T) conditions recorded by rocks in the massif, and the time (t) at which they achieved those conditions. However, limited P-T-t data exists in the Southern Menderes Massif. Here, P-T-t data was obtained from garnet-bearing rocks collected perpendicular to strike along seven transects spaced about 35 km across the Selimiye Shear Zone. Garnets in nine samples from four transects were analyzed using high-resolution back-scattered electron (BSE) imagery, X-ray element (Fe, Mg, Mn, Ca and Y) maps, and quantitative compositional analyses. Both zircon and monazite grains were dated in rock thin section using Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) and Secondary Ion Mass Spectrometry (SIMS) to ascertain the timing of events recorded by the rocks. Some garnet X-ray element maps show zoning consistent with multiple stages of growth, diffusion, and retrogression. Distinct zones in each sample are visible on high contrast BSE images and can be related to Y, Fe, and Mn contents. The conventional garnet + biotite geothermometer and garnet + plagioclase + muscovite + biotite geobarometer were used to estimate peak metamorphic P-T conditions. These range from 556±10°C to 671±27°C, and 15.3±0.2 kbar to 22.4±0.5 kbar. The temperatures are similar to previous estimates, but the pressures appear about ~10 kbar higher the previous estimates. U-Pb zircon ages range from 2022±30 Ma (13.4% disc.) to 254±5 Ma (13.4% disc.). Based on Th/U contents, the oldest ages are likely related to inherited grains from magmatic sources. The youngest zircon age is the first reported Triassic grain from the Southern Menderes Massif and may relate to the closure event of the Paleo-Tethyan Ocean. A younger history is recorded by U-Pb and Th-Pb monazite ages, which range Cretaceous to Miocene. Monazite geochronology is hindered by the contamination of high amounts of common Pb, but U-Pb and Th-Pb age calculations show Miocene to Jurassic ages. The textures of monazite (i.e. drusy, filling cracks of garnet and in reaction with allanite) imply that ages could record crystallization and/or fluid dissolution/reprecipitation mediated events in the Oligocene. Data reported here support the observation that polymetamorphic events are recorded in the Southern Menderes Massif rocks in close proximity to the Selimiye Shear Zone. Two options are possible environments of continental exhumation of rocks along the zone: (1) a polymetamorphic history that records relict high-pressures from previous metamorphic events or (2) a single-stage exhumation of high-pressure rocks. / text

The Aegean region contains numerous metamorphic core complexes that reflect post-collision extensional tectonics. The largest of these is the Menderes Massif of western Turkey, which covers an area of ~40,000 km². The Selimiye Shear Zone bounds its southern border and is a key location for studying the metamorphic history of the massif. Models of the tectonic evolution of the region requires an understanding of the peak pressure-temperature (P-T) conditions recorded by rocks in the massif, and the time (t) at which they achieved those conditions. However, limited P-T-t data exists in the Southern Menderes Massif. Here, P-T-t data was obtained from garnet-bearing rocks collected perpendicular to strike along seven transects spaced about 35 km across the Selimiye Shear Zone. Garnets in nine samples from four transects were analyzed using high-resolution back-scattered electron (BSE) imagery, X-ray element (Fe, Mg, Mn, Ca and Y) maps, and quantitative compositional analyses. Both zircon and monazite grains were dated in rock thin section using Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS) and Secondary Ion Mass Spectrometry (SIMS) to ascertain the timing of events recorded by the rocks. Some garnet X-ray element maps show zoning consistent with multiple stages of growth, diffusion, and retrogression. Distinct zones in each sample are visible on high contrast BSE images and can be related to Y, Fe, and Mn contents. The conventional garnet + biotite geothermometer and garnet + plagioclase + muscovite + biotite geobarometer were used to estimate peak metamorphic P-T conditions. These range from 556±10°C to 671±27°C, and 15.3±0.2 kbar to 22.4±0.5 kbar. The temperatures are similar to previous estimates, but the pressures appear about ~10 kbar higher the previous estimates. U-Pb zircon ages range from 2022±30 Ma (13.4% disc.) to 254±5 Ma (13.4% disc.). Based on Th/U contents, the oldest ages are likely related to inherited grains from magmatic sources. The youngest zircon age is the first reported Triassic grain from the Southern Menderes Massif and may relate to the closure event of the Paleo-Tethyan Ocean. A younger history is recorded by U-Pb and Th-Pb monazite ages, which range Cretaceous to Miocene. Monazite geochronology is hindered by the contamination of high amounts of common Pb, but U-Pb and Th-Pb age calculations show Miocene to Jurassic ages. The textures of monazite (i.e. drusy, filling cracks of garnet and in reaction with allanite) imply that ages could record crystallization and/or fluid dissolution/reprecipitation mediated events in the Oligocene. Data reported here support the observation that polymetamorphic events are recorded in the Southern Menderes Massif rocks in close proximity to the Selimiye Shear Zone. Two options are possible environments of continental exhumation of rocks along the zone: (1) a polymetamorphic history that records relict high-pressures from previous metamorphic events or (2) a single-stage exhumation of high-pressure rocks. / text

Proefschrift Universiteit van Amsterdam. / Met lit. opg., bibliogr. van de auteur en samenvatting in het Nederlands.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted.

Thesis (doctoral)--Lund University, 1998. / Added t.p. with thesis statement inserted.

Zugl.: München, Univ., Diss., 2008

Thesis (doctoral)--Universiteit van Amsterdam. / Summary in German. Bibliography of J.T. Beck's works: p. 23-25. Includes bibliographical references and index.