Core B will provide materials and carry out functions essential for Projects 1-3 of this Program Project. The functions include the synthesis of peptides, peptidomimetics, as well as natural and modified gangliosides that are required for the investigations described in the individual projects. These materials will be used for cocrystallization structural studies and in the biological function and biochemical screening assays detailed here. In addition, the core will provide labeled (e.g., fluorescently tagged) saccharides/gangliosides for biochemical and functional assays necessary to probe the mechanism of action of the molecular inhibitors developed in this Program Project. Peptide domains of the serotonin 5HT2a receptor will be synthesized as part of Project #2, to investigate the development of inhibitors of the initial association for viral entry. Within the core, small well focused peptide and peptidomimetic libraries will be synthesized for the screening assays detailed in Project #3. The hits identified from these screening efforts will be scaled up within the Core for functional characterization with respect to viral infection (Project #2) and co-crystallization studies with the VPl protein (Project #1). Using the latest techniques for the preparative purification of peptides and gangliosides, we will provide 1 to 100mg of highly purified material to support investigations carried out in the Projects. All of the materials will be extensively characterized by the techniques available to the Core, including MS, HPLC, and NMR. These techniques plus CD, fluorescence, FPLC, ITC, and dynamic light scattering are available within the Core for indepth analytical characterization of peptides/proteins generated within the individual projects. The Core provides both state-of-the-art instrumentation and highly trained investigators and support personnel to carry out these research efforts.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS065719-05
Application #
8512821
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$195,013
Indirect Cost
Name
Brown University
Department
Type
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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Haley, Sheila A; O'Hara, Bethany A; Nelson, Christian D S et al. (2015) Human polyomavirus receptor distribution in brain parenchyma contrasts with receptor distribution in kidney and choroid plexus. Am J Pathol 185:2246-58
Nelson, Christian D S; Ströh, Luisa J; Gee, Gretchen V et al. (2015) Modulation of a pore in the capsid of JC polyomavirus reduces infectivity and prevents exposure of the minor capsid proteins. J Virol 89:3910-21
Haley, Sheila A; Atwood, Walter J (2014) An animal model for progressive multifocal leukoencephalopathy. J Clin Invest 124:5103-6
Zins, Stephen R; Nelson, Christian D S; Maginnis, Melissa S et al. (2014) The human alpha defensin HD5 neutralizes JC polyomavirus infection by reducing endoplasmic reticulum traffic and stabilizing the viral capsid. J Virol 88:948-60

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