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The Role of Phospholipase D2 in golgi-architecture maintenance, vesicular trafficking and glucose- stimulated insulin release & Validation of a novel non- invasive approach to functional β-cell mass quantification

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dc.contributor.advisor Frohman, Michael A. en_US
dc.contributor.author Yeku, Oladapo Olumoroti en_US
dc.contributor.other Department of Molecular and Cellular Pharmacology en_US
dc.date.accessioned 2012-05-15T18:07:32Z
dc.date.available 2012-05-15T18:07:32Z
dc.date.issued 1-Aug-10 en_US
dc.date.submitted Aug-10 en_US
dc.identifier Yeku_grad.sunysb_0771E_10220.pdf en_US
dc.identifier.uri http://hdl.handle.net/1951/55681
dc.description.abstract Phospholipase D (PLD) is essential for different aspects of vesicle trafficking and regulated exocytosis in a variety of biological models. PLD1 and PLD2 are the two major mammalian isoforms and both isoforms localize to different organelles where they generate phosphatidic acid (PA), the effector molecule of PLD activity. The role of PLD1 in glucose-stimulated insulin release (GSIR), a form of regulated exocytosis, has been well characterized. Additionally, the role of PLD1 in anterograde vesicle trafficking from the ER to the cis-golgi and from the trans-golgi to the plasma membrane has also been described. The role of PLD2 in GSIR and vesicle trafficking has been less defined. Here we report an essential role for PLD2 in cis-golgi architecture maintenance and GSIR. Loss of PLD2 leads to increased GSIR and tubulated cis-golgi morphology. Dysregulation of Ca<super>2+</super> homeostasis was found to be responsible for increased GSIR in PLD2 knockdown cells. We further identified a putative lipid sensor and phosphatidic acid phosphatase (PAP), PITPNM3, that plays a role downstream of PLD2 activity to support golgi architecture. For the first time, we suggest a role for PA to DAG conversion as an integral process for cis-golgi architecture maintenance. Finally, in insulin- secreting cells, we provide evidence that supports opposing roles for PLD1 and PLD2 in golgi architecture maintenance and GSIR. In renal epithelial cells, we found cis-golgi fragmentation and lysosomal trafficking defects when PLD2 was knocked down. Examination of PLD2<super>-/-</super> mouse kidneys showed vacuolization of the proximal tubules without any measurable decline in renal function.Failure of insulin secretion by&#914;-cells is the underlying cause of type-I diabetes. To date, there is no way to monitor functional&#914;-cell mass non-invasively. Here we demonstrate a proof of principle approach to the detection and quantification of functional&#914;-cell mass using an established metabolomic approach. en_US
dc.description.sponsorship Stony Brook University Libraries. SBU Graduate School in Department of Molecular and Cellular Pharmacology. Lawrence Martin (Dean of Graduate School). en_US
dc.format Electronic Resource en_US
dc.language.iso en_US en_US
dc.publisher The Graduate School, Stony Brook University: Stony Brook, NY. en_US
dc.subject.lcsh Biology, Cell en_US
dc.subject.other Diabetes, Golgi, NMR, PLD, PLD2, Vesicular Trafficking en_US
dc.title The Role of Phospholipase D2 in golgi-architecture maintenance, vesicular trafficking and glucose- stimulated insulin release & Validation of a novel non- invasive approach to functional &#946;-cell mass quantification en_US
dc.type Dissertation en_US
dc.description.advisor Advisor(s): Michael A. Frohman. Committee Member(s): David Talmage; Ken-Ichi Takemaru; Richard Z. Lin. en_US
dc.mimetype Application/PDF en_US


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