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.
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.
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