Small, high-affinity ligands for array tomography

DESCRIPTION provided by applicant Neurodegenerative diseases are among the most expensive disruptive and least well treated of human maladies arguably because they are not well understood Array tomography AT is a method for tissue imaging with resolution in
all three dimensions sufficient to resolve individual synapses and provide quantitative characterization of multiple molecular constituents AT imaging data enable description of neural networks in the context of the three dimensional tissue architecture We beleve such data will enable researchers to begin to comprehend the proper function of neural circuits and importantly to begin to understand how it is that the various neurodegenerative processes present and progress AT is however complex and expensive and has been used in relatively few studies following the first publication in by Micheva and Smith Aratome is currently providing AT services to the research community The present application proposes proof of concept studies that a novel ligand development approach can be used to make ligands for AT that are superior to primary antibodies in that they can be bacterially expressed which would make the reagents relatively inexpensive and of uniform quality and they are very small amino acis so that they will likely have greater access to target binding motifs which is a major problem with the resin embedded tissue used for AT Assuming we obtain proof of
concept under the present Phase proposal we would develop a catalog of reagents in Phase which would be made generally available and which would be integrated into a fully automated AT system analogous to a NextGen Sequencer that we are developing using separate funding

PUBLIC HEALTH RELEVANCE Neurodegenerative diseases including Alzheimerandapos s and Parkinsonandapos s are becoming increasingly prevalent as the average population ages Efforts to develop treatments for these diseases have been hampered by a lack of basic understanding of the disease processes due in part to the lack of technologies that provide quantitative information regarding disease progression We propose a the development of reagents that will enable fully automated high resolution proteomic analysis of he brain to better understand these pathologies which should enable the development of more effective treatments