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 #
5P41GM103314-44
Application #
9233741
Study Section
Special Emphasis Panel (ZRG1-BCMB-K (40)P)
Program Officer
Sheeley, Douglas
Project Start
1996-12-23
Project End
2018-02-28
Budget Start
2017-03-01
Budget End
2018-02-28
Support Year
44
Fiscal Year
2017
Total Cost
$1,455,472
Indirect Cost
$594,572
Name
Rockefeller University
Department
Miscellaneous
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Delgado-Benito, VerĂ³nica; Rosen, Daniel B; Wang, Qiao et al. (2018) The Chromatin Reader ZMYND8 Regulates Igh Enhancers to Promote Immunoglobulin Class Switch Recombination. Mol Cell 72:636-649.e8
Jishage, Miki; Yu, Xiaodi; Shi, Yi et al. (2018) Architecture of Pol II(G) and molecular mechanism of transcription regulation by Gdown1. Nat Struct Mol Biol 25:859-867
Kim, Seung Joong; Fernandez-Martinez, Javier; Nudelman, Ilona et al. (2018) Integrative structure and functional anatomy of a nuclear pore complex. Nature 555:475-482
Kleiner, Ralph E; Hang, Lisa E; Molloy, Kelly R et al. (2018) A Chemical Proteomics Approach to Reveal Direct Protein-Protein Interactions in Living Cells. Cell Chem Biol 25:110-120.e3
Sanghai, Zahra Assur; Miller, Linamarie; Molloy, Kelly R et al. (2018) Modular assembly of the nucleolar pre-60S ribosomal subunit. Nature 556:126-129
Winczura, Kinga; Schmid, Manfred; Iasillo, Claudia et al. (2018) Characterizing ZC3H18, a Multi-domain Protein at the Interface of RNA Production and Destruction Decisions. Cell Rep 22:44-58
Holden, Jennifer M; Koreny, Ludek; Obado, Samson et al. (2018) Involvement in surface antigen expression by a moonlighting FG-repeat nucleoporin in trypanosomes. Mol Biol Cell 29:1100-1110
Taylor, Martin S; Altukhov, Ilya; Molloy, Kelly R et al. (2018) Dissection of affinity captured LINE-1 macromolecular complexes. Elife 7:
Chan, Ho Lam; Beckedorff, Felipe; Zhang, Yusheng et al. (2018) Polycomb complexes associate with enhancers and promote oncogenic transcriptional programs in cancer through multiple mechanisms. Nat Commun 9:3377
Schrank, Benjamin R; Aparicio, Tomas; Li, Yinyin et al. (2018) Nuclear ARP2/3 drives DNA break clustering for homology-directed repair. Nature 559:61-66

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