1996 — 1999 |
Wiedmer, Therese |
P01Activity Code Description: For the support of a broadly based, multidisciplinary, often long-term research program which has a specific major objective or a basic theme. A program project generally involves the organized efforts of relatively large groups, members of which are conducting research projects designed to elucidate the various aspects or components of this objective. Each research project is usually under the leadership of an established investigator. The grant can provide support for certain basic resources used by these groups in the program, including clinical components, the sharing of which facilitates the total research effort. A program project is directed toward a range of problems having a central research focus, in contrast to the usually narrower thrust of the traditional research project. Each project supported through this mechanism should contribute or be directly related to the common theme of the total research effort. These scientifically meritorious projects should demonstrate an essential element of unity and interdependence, i.e., a system of research activities and projects directed toward a well-defined research program goal. |
Cell Components Regulating Phosphatidylserine Exposure @ Bloodcenter of Wisconsin, Inc.
surface property; tissue /cell culture
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0.933 |
1998 — 2001 |
Wiedmer, Therese |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Molecular Basis of the Platelet Storage Lesion @ Scripps Research Institute
Collection and in vitro storage of blood platelets results in the progressive movement of phosphatidylserine (PS) and phosphatidylethanolamine (PE) from inner to outer leaflet of the platelet plasma membrane. This loss of normal plasma membrane phospholipid (PL) asymmetry with exposure of these aminophospholipids on the platelet surface is implicated in the formation of thrombin, in the activation of complement, and in hepato-splenic sequestration and accelerated clearance of platelets following transfusion. This Project aims to identify the mechanism(s) responsible for this abnormal transbilayer movement of plasma membrane phospholipids in stored platelets and to deduce conditions of storage that will preserve normal sequestration of PS and PE to the inner leaflet. The Specific Aims include: (1) To determine whether the progressive movement of PS to the surface of platelets during storage in autologous plasma reflects membrane reorganization induced through mechanical shear, a decrease in activity of the platelet plasma membrane aminophospholipid translocase, and/or inappropriate activation of the platelet plasma membrane phospholipid scramblase; (2) To determine the relative contributions of altered cytosolic Ca2+, ATP, and pH to the accelerated transbilayer movement of platelet plasma membrane phospholipids; (3) To determine how oxidative changes in either PL scramblase or aminophospholipid translocase during cell storage affect transbilayer distribution of plasma membrane phospholipids; (4) To determine the role of plasma components contained in platelet concentrates to the accelerated movement of aminophospholipids to the platelet surface. Of particular interest is the role of thrombin, plasmin and the C5b-9 components of complement; (5) To identify storage conditions optimized to maintain the normal sequestration of platelet plasma membrane aminophospholipids. Those conditions are considered optimal that maximize the activity of aminophospholipid traslocase and minimize that of the intracellular Ca2+-activated PL scramblase.
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0.906 |
2004 — 2007 |
Wiedmer, Therese |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Role of Plscr in Cell Response to Growth Factors @ Scripps Research Institute
[unreadable] DESCRIPTION (provided by applicant): Phospholipid scramblase 1 (PLSCR1) is a multiply palmitoylated, endofacial plasma membrane protein first identified in red cells, platelets, leukocytes, and other blood cells, which is thought to mediate the transbilayer movement of membrane phospholipids in response to cell activation, injury, or apoptosis. PLSCR1 has been found associated with several growth factor receptors, including epidermal growth factor receptor (EGF-R). PLSCR1 expression is transcriptionally induced by EGF and related growth factors, and it is phosphorylated by tyrosine kinases that are involved in the signal transduction pathways initiated through EGF-R and related receptors. We recently observed that newly synthesized PLSCR1 can localize to the nucleus, and we found nuclear import of PLSCR1 to occur whenever the polypeptide fails to palmitoylate. By contrast, palmitoylated PLSCR1 is a component of plasma membrane lipid "rafts", cholesterol- and sphingomyelin-rich membrane microdomains that are believed to be involved in both assembly of receptor signaling platforms and the endocytic trafficking of activated EGF-R and related receptors from the plasma membrane. We also observed that neutrophil production and maturation in response to select growth factors is impaired in PLSCR1-/-mice, whereas fibroblasts and epithelial cells from these animals exhibit attenuated responses to EGF and related growth factors, with particular effect on EGF-dependent activation of c-Src. In this Project, we aim to elucidate the role of PLSCR1 in the signaling pathways of EGF-R and related growth factor receptors. Our Specific Aims are: Aim1 -- To determine whether the level of expression of plasma membrane PLSCR1 influences cell surface expression, topology, sensitivity to ligand, and/or receptor-initiated activation of signaling kinases by EGF and related growth factors. AIM2 -- To determine whether PLSCR1 influences the localization of EGF-R to membrane lipid rafts, its interactions with key adaptor proteins and signaling kinases, or its endocytic uptake, endosomal trafficking, and degradation following receptor activation. AIM3 - To identify the mechanism by which PLSCR1 traffics into the nucleus, and to determine what role nuclear PLSCR1 might play in the cellular transcription response to cytokine stimulation. We believe that this research will provide new insights into the regulatory control mechanisms that affect signaling by activated growth factor receptors. [unreadable] [unreadable]
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