Dr. P. Fernando M. Teran-Arce’s laboratory uses various modalities of atomic force microscopy (AFM), complemented by biophysical and optical techniques, to investigate the mechanical and structural mechanisms underlying pathobiological processes in neurodegenerative and bacterial diseases, as well as pulmonary injury.
Amyloids, proteins abnormally folded into β-sheet conformations from their native configurations, are implicated in a variety of protein misfolding diseases, including Alzheimer's and Parkinson's. These diseases are primarily characterized by the self-assembly of amyloids into fibrillar structures. Growing evidence indicates, however, that smaller oligomeric structures are primarily responsible for toxicity. His previous work has contributed to a better understanding of the pore mechanism of amyloid-β (Aβ) toxicity. AFM-related techniques provide structural details of amyloid fibrillar structures, phase-separated lipid domains, Aβ oligomers bound to lipid bilayers and membrane-inserted pore structures. This structural information, together with molecular dynamics simulations and planar lipid bilayer electrical recording has provided structural and functional relationships of the membrane-bound peptides. In addition to leading to a better understanding of AD mechanisms, this work aims to provide pharmaceutical targets for AD patients.
The effect of amyloids on the mechanical properties of cell membranes is not well understood. Amyloid fibrils have a mechanical strength comparable to steel (~ 1 GPa), due to their high content of β-sheets. It has been suggested that these stiff fibrils distort or penetrate the membrane, leading to cell death. Even though amyloid oligomers are generally believed to be more toxic than fibrils, the mechanical properties of oligomers inserted in membranes have seldom been investigated. Dr. Teran-Arce plans to use AFM to probe the mechanical properties of model membranes reconstituted with amyloid oligomers, and thereby gain information about their structure in the membrane. He also is working to develop novel force-sensing techniques to increase the applicability and force sensitivity of AFM.
In addition to nanomechanical studies, high-resolution AFM imaging is used to examine the nanoscale structural changes in the membrane as a result of their interaction with Aβ oligomers. Dr. Teran-Arce uses planar lipid bilayer electrical recording to measure the pore activity of membrane-inserted Aβs. A future goal is to combine electrical recording with structural imaging to simultaneously obtain structural and functional data. The techniques resulting from this work will be applied to investigate pathobiological mechanisms in pulmonary vascular diseases in collaboration with several labs at the Division of Translational and Regenerative Medicine, including Dr. Yuan's, Dr. Garcia's and Dr. Black's labs.