Mechanistic Investigations into ADRD Associated Protein Structures in Biological Settings (R01 - Clinical Trial Not Allowed)
The grant titled "Mechanistic Investigations into ADRD Associated Protein Structures in Biological Settings" aims to use recent advancements in structural biology to study protein assemblies related to Alzheimer's disease and related dementias (AD/ADRD) in their natural environments within cells and tissues, with the goal of developing ligands that can identify and monitor these proteins in patients.
Description
Advances in structural biology have enabled the characterization of large protein assemblies that are linked to AD/ADRD pathology. However, most structural biology approaches require purified samples from cells and tissues or use recombinant bacterial proteins. The derived structures using ex-vivo material may not report the diversity of physiologically relevant species because reconstruction relies on class averaging that is biased towards dominant conformations that survive methodological processing. Recent developments in structural biology offer the possibility of in situ characterization of specific macromolecular assemblies. Structural information of protein assemblies and aggregates in their native cellular and tissue environments could facilitate rational structure-based ligand development. Currently, PET ligands that specifically identify and monitor the accumulation of aggregated and misfolded proteins in AD/ADRD patients are lacking.