Protein conformational diseases, including neurodegenerative (Alzheimer's and Parkinson's diseases), type II diabetes and cystic fibrosis result from protein misfolding that alters their 3D conformations from native (soluble) to non-native (insoluble) folded structures, called amyloids. Understanding such misfolding and the resulting 3D conformations that induce pathophysiological cellular activity and degeneration have been one of the most important and yet challenging areas of research. The original idea suggests that misfolding-induced fibrillar structure results into a gain-of-function and induce pathophysiology by altering cell membrane composition via free radical oxidative stress and/or non-specific membrane leakage and thence destabilizing ionic homeostasis. However, recent studies show that globular, non-fibrillar macromolecular complexes are sufficient to induce cell pathology, presumably directly by their membrane poration. Indeed, small monomeric and oligomeric peptides are reported to induce ionic conductances in artificial as well as native cell membranes. 3D structure and ligand-induced conformational changes of these putative ion channels are poorly understood. An understanding of the 3-D structure of amyloidogenic peptide-channel and its role in cell toxicity is essential for designing counteracting drugs and rational strategies for treatment of conformational diseases. This proposal aims to examine hypothesis-driven questions about protein conformational diseases and also design techniques to accomplish the goals. Our overall hypothesis is that protein misfolding diseases result from their globular (not fibrillar) conformation that forms ion channels and molecules and that other interventions, to modulate their structure and activity, could be used for effective therapy. We propose the following Specific Aims: 1: examine 3D ion-channel structure of globular amyloidogenic peptides reconstituted in lipid membrane;2: Examine open-closed channel conformations in response to various pharmacological agents and peptides;3: correlate channel open-close conformations with channel conductance using a combined AFM-ion conductance measurement system and pharmacological agents. Thus we aim to provide a unique and feasible model system for screening putative drug molecules and designing therapeutics for a wide range of degenerative diseases that result from defects in ion channel structure and activity, the """"""""channelopathies"""""""".

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
3R01AG028709-06S1
Application #
8531447
Study Section
Special Emphasis Panel (ZRG1-BDCN-F (11))
Program Officer
Refolo, Lorenzo
Project Start
2006-09-15
Project End
2013-02-28
Budget Start
2012-09-01
Budget End
2013-02-28
Support Year
6
Fiscal Year
2012
Total Cost
$155,000
Indirect Cost
$55,000
Name
University of California San Diego
Department
Engineering (All Types)
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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