Project Summary/Abstract Funds are requested to purchase a Leica ARTOS ultramicrotome with necessary accessories including a vibration isolation instrument table, diamond knives, and a glass knifemaker. Included with the purchase will be training for the major users and the core facility staff member responsible for overseeing use of the instrument. The instrument will be housed in the campus Molecular Cytology Core Facility (MCC) where it will replace an ultramicrotome that is over 30 years old and in disrepair. The existing instrument can no longer be serviced due to its age and lack of replacement parts. The ultramicrotome is essential for the research being conducted by members of a large user group. Research by the users that requires this instrument includes studies on hereditary neurodegenerative and retinal degenerative diseases, amyotrophic lateral sclerosis, dry eye diseases, connective tissue disorders, lysosomal storage diseases and cancer. The new instrument will enable the investigators to prepare tissue sections for both light and electron microscopic (EM) examination. The instrument will enable users to produce ribbons of serial sections that can be used to generate 3- dimensional images of tissues and cellular structures of interest using advanced light microscopy equipment (including confocal microscopes) at the MCC and electron microscopy capabilities of the University Electron Microscopy Core Facility (EMC) to obtain images for array tomography. The 3-D images will enable the investigators to address important research questions that cannot be addressed using microtomy instrumentation currently available at the University. For example, it appears that impaired retinal function in several hereditary disorders under investigation may be due to alterations in the synapses between retinal neurons. It is very difficult to determine whether this is the case by examining individual thin sections with TEM or with immunofluorescence (IF) using confocal microscopy alone. If the users can collect serial sections encompassing entire synaptic structures and generate 3-D composite images that can be examined with both EM and immunofluorescence, the users will be able to reliably determine whether there are disease-related structural alterations in the synapses that could explain the functional deficits. Numerous projects of anticipated users would benefit from having the capability of performing correlative IF and EM with array tomography. The information that users will be able to glean using the ultramicrotome will assist in developing better understanding of pathogenesis and in developing effective therapies for numerous disorders. In addition to benefiting the biomedical research of users that are identified in this proposal, the ultramicrotome has the potential to facilitate the research of additional potential biomedical researchers. Many laboratories utilize the MCC for a variety of microscopy techniques and digital image processing....