Abstract

This is a proposal to combine two-dimensional infrared spectroscopy with oxidative footprinting / mass spectrometry and molecular mechanics simulation to answer key questions about the formation and structure of amyloid beta protein fibrils. There are two specific aims: 1. Correlate structure and morphology in amyloid fibrils. 2. Characterize the development of structure in oligomeric forms of A?. This project is an interdisciplinary collaboration between a physician-pharmacologist investigating the pathology of Alzheimer's disease, and a chemical physicist pioneering novel spectroscopic methods. We will be applying an emerging, powerful, and versatile technology for the first time to understanding the structural biology of an important biomedical problem. This research will make use of instrumentation in the Ultrafast Optical Processes Laboratory - an NIH Research Resource at the University of Pennsylvania. This laboratory was established to develop novel technologies involving infrared spectroscopy for the study of biological macromolecules, and to make advanced instrumentation and expertise available for collaborative projects of this type.

Public Health Relevance

This is a proposal to combine two-dimensional infrared spectroscopy with oxidative footprinting / mass spectrometry and molecular mechanics simulation to answer key questions about the formation and structure of amyloid beta protein fibrils.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM076201-05
Application #
8151076
Study Section
Macromolecular Structure and Function C Study Section (MSFC)
Program Officer
Smith, Ward
Project Start
2007-04-15
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
5
Fiscal Year
2011
Total Cost
$311,725
Indirect Cost

  Institution

Name
University of Pennsylvania
Department
Pharmacology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104

  Publications

Furman, Ran; Lee, Jin V; Axelsen, Paul H (2018) Analysis of eicosanoid oxidation products in Alzheimer brain by LC-MS with uniformly 13C-labeled internal standards. Free Radic Biol Med 118:108-118
Grasso, Giuseppe; Axelsen, Paul H (2017) Effects of covalent modification by 4-hydroxy-2-nonenal on the noncovalent oligomerization of ubiquitin. J Mass Spectrom 52:36-42
Lee, Jin V; Furman, Ran; Axelsen, Paul H (2017) Biosynthesis of uniformly labeled13C- and14C-arachidonic acid in Mortierella alpina. Bioresour Technol 227:142-146
Eskici, Gözde; Axelsen, Paul H (2016) The Size of AOT Reverse Micelles. J Phys Chem B 120:11337-11347
Furman, Ran; Murray, Ian V J; Schall, Hayley E et al. (2016) Amyloid Plaque-Associated Oxidative Degradation of Uniformly Radiolabeled Arachidonic Acid. ACS Chem Neurosci 7:367-77
Klinger, Alexandra L; Kiselar, Janna; Ilchenko, Serguei et al. (2014) A synchrotron-based hydroxyl radical footprinting analysis of amyloid fibrils and prefibrillar intermediates with residue-specific resolution. Biochemistry 53:7724-34
Yeung, Priscilla S-W; Eskici, Gözde; Axelsen, Paul H (2013) Infrared spectroscopy of proteins in reverse micelles. Biochim Biophys Acta 1828:2314-8
Ma, Jianqiang; Komatsu, Hiroaki; Kim, Yung Sam et al. (2013) Intrinsic structural heterogeneity and long-term maturation of amyloid ? peptide fibrils. ACS Chem Neurosci 4:1236-43
Yeung, Priscilla S-W; Axelsen, Paul H (2012) The crowded environment of a reverse micelle induces the formation of ?-strand seed structures for nucleating amyloid fibril formation. J Am Chem Soc 134:6061-3
Kim, Yung Sam; Liu, Liu; Axelsen, Paul H et al. (2009) 2D IR provides evidence for mobile water molecules in beta-amyloid fibrils. Proc Natl Acad Sci U S A 106:17751-6

Showing the most recent 10 out of 11 publications