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 #
2P41GM103314-40
Application #
8477503
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
2013-05-10
Budget End
2014-02-28
Support Year
40
Fiscal Year
2013
Total Cost
$2,320,963
Indirect Cost
$638,286
Name
Rockefeller University
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Subbotin, Roman I; Chait, Brian T (2014) A pipeline for determining protein-protein interactions and proximities in the cellular milieu. Mol Cell Proteomics 13:2824-35
Anand, Prachi; Grigoryan, Alexandre; Bhuiyan, Mohammed H et al. (2014) Sample limited characterization of a novel disulfide-rich venom peptide toxin from terebrid marine snail Terebra variegata. PLoS One 9:e94122
Li, Yinyin; Cross, Frederick R; Chait, Brian T (2014) Method for identifying phosphorylated substrates of specific cyclin/cyclin-dependent kinase complexes. Proc Natl Acad Sci U S A 111:11323-8
Algret, Romain; Fernandez-Martinez, Javier; Shi, Yi et al. (2014) Molecular architecture and function of the SEA complex, a modulator of the TORC1 pathway. Mol Cell Proteomics 13:2855-70
Shi, Yi; Fernandez-Martinez, Javier; Tjioe, Elina et al. (2014) Structural characterization by cross-linking reveals the detailed architecture of a coatomer-related heptameric module from the nuclear pore complex. Mol Cell Proteomics 13:2927-43
Zhong, Yu; Morris, Deanna H; Jin, Lin et al. (2014) Nrbf2 protein suppresses autophagy by modulating Atg14L protein-containing Beclin 1-Vps34 complex architecture and reducing intracellular phosphatidylinositol-3 phosphate levels. J Biol Chem 289:26021-37
Fridy, Peter C; Li, Yinyin; Keegan, Sarah et al. (2014) A robust pipeline for rapid production of versatile nanobody repertoires. Nat Methods 11:1253-60
Cevher, Murat A; Shi, Yi; Li, Dan et al. (2014) Reconstitution of active human core Mediator complex reveals a critical role of the MED14 subunit. Nat Struct Mol Biol 21:1028-34
Holden, Jennifer M; Koreny, Ludek; Obado, Samson et al. (2014) Nuclear pore complex evolution: a trypanosome Mlp analogue functions in chromosomal segregation but lacks transcriptional barrier activity. Mol Biol Cell 25:1421-36
Holden, Jennifer M; Koreny, Ludek; Kelly, Steven et al. (2014) Touching from a distance: Evolution of interplay between the nuclear pore complex, nuclear basket, and the mitotic spindle. Nucleus 5:

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