It is proposed to continue to operate and extend the cutting edge capabilities of the National Resource for the Mass Spectrometric Analysis of Biological Macromolecules for years 40 through 44. Emphasis will be placed on developing mass spectrometric technology for analyzing peptides and proteins in order to elucidate fundamental biological processes that underlie both normal physiology and diseases that include AIDS, hepatitis C infection, drug addiction, chronic pain, cancer, bacterial infection, typ-2 diabetes, Alzheimer's disease, Parkinson's disease, sleeping sickness, and neuronal degeneration. The major subdivisions of the Resource are: Technological Research &Development (TR&D), Driving Biological Projects (DBPs), Collaboration &Service, Dissemination, and Education. Our three TR&D aims are: (1) Instrument development for increasing sensitivity and signal-to-noise, (2) Methodology development for elucidating 4-dimensional cellular interactomes and (3) Methodology development for elucidating complex high diversity systems including toxins and antibodies. Our DBPs will seek to (1) gain an understanding of broadly neutralizing anti-HIV antibodies;(2) develop improved methods for elucidating the structures of conotoxins as potential therapeutics;(3) profile neuropeptides in th CNS and peripheral circulation;(4) define the HIV-1 interactome;(5) define viral and host-derived proteins incorporated into HCV particles;(6) investigate a new tumor suppressor pathway in lymphoma;(7) elucidate the fine structure of the nuclear pore complex;(8) elucidate the biosynthetic pathway of S. aureus autoinducing peptide;(9) elucidate the biomolecular anatomy of inhibitory synapses;and (10) analyze the cellular response to DNA double-strand breaks. Our collaborations will seek to investigate: (1) African trypanosome proteins at the host-parasite interface and develop tools for proteomic analysis in trypanosomes;(2) autophagy protein complexes in animal models;(3) cyclin dependent kinase substrates;(4) mechanisms of nucleotide excision repair;(5) human L1 function;(7) mediator-dependent transcription;(8) islet amyloid formation;(9) structure of the transmembrane Type III secretion system needle;and (10) structure of the herpes simplex virus.

Public Health Relevance

It is planned to develop enabling mass spectrometric tools for elucidating fundamental biological processes that underlie both normal physiology and diseases that include AIDS, hepatitis C infection, drug addiction, chronic pain, cancer, bacterial infection type-2 diabetes, Alzheimer's disease, Parkinson's disease, sleeping sickness, and neuronal degeneration.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Biotechnology Resource Grants (P41)
Project #
5P41GM103314-41
Application #
8660308
Study Section
Special Emphasis Panel (ZRG1-BCMB-K (40))
Program Officer
Sheeley, Douglas
Project Start
1996-12-23
Project End
2018-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
41
Fiscal Year
2014
Total Cost
$1,410,633
Indirect Cost
$575,076
Name
Rockefeller University
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
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Santanach, Alexandra; Blanco, Enrique; Jiang, Hua et al. (2017) The Polycomb group protein CBX6 is an essential regulator of embryonic stem cell identity. Nat Commun 8:1235
Upla, Paula; Kim, Seung Joong; Sampathkumar, Parthasarathy et al. (2017) Molecular Architecture of the Major Membrane Ring Component of the Nuclear Pore Complex. Structure 25:434-445
Kang, Jin Young; Olinares, Paul Dominic B; Chen, James et al. (2017) Structural basis of transcription arrest by coliphage HK022 Nun in an Escherichia coli RNA polymerase elongation complex. Elife 6:
Wang, Boyuan; Zhao, Aishan; Xie, Qian et al. (2017) Functional Plasticity of the AgrC Receptor Histidine Kinase Required for Staphylococcal Virulence. Cell Chem Biol 24:76-86
Chait, Brian T; Cadene, Martine; Olinares, Paul Dominic et al. (2016) Revealing Higher Order Protein Structure Using Mass Spectrometry. J Am Soc Mass Spectrom 27:952-65
Rivera-Torres, Iván O; Jin, Tony B; Cadene, Martine et al. (2016) Discovery and characterisation of a novel toxin from Dendroaspis angusticeps, named Tx7335, that activates the potassium channel KcsA. Sci Rep 6:23904
Lussignol, Marion; Kopp, Martina; Molloy, Kelly et al. (2016) Proteomics of HCV virions reveals an essential role for the nucleoporin Nup98 in virus morphogenesis. Proc Natl Acad Sci U S A 113:2484-9
Obado, Samson O; Brillantes, Marc; Uryu, Kunihiro et al. (2016) Interactome Mapping Reveals the Evolutionary History of the Nuclear Pore Complex. PLoS Biol 14:e1002365
Obado, Samson O; Field, Mark C; Chait, Brian T et al. (2016) High-Efficiency Isolation of Nuclear Envelope Protein Complexes from Trypanosomes. Methods Mol Biol 1411:67-80

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