We propose to develop a core facility focused on Synthetic Molecular Probes for In Vivo Imaging (SMP, Core-C). SMP Core-C will provide investigators with novel chemical probes of biological systems and offer fluorescence-based imaging of dynamic aspects of physiology and pathology in living model organisms. This core facility will expand the existing imaging infrastructure at KU by bridging a gap that currently exists between very high resolution imaging of cells in culture and low resolution imaging of fluorescent tracers in rodents. By acquiring modern fluorescence dissecting microscopy equipment equipped with integrated microinjection capability, our investigators will gain new abilities to discover and manipulate dynamic biological processes in small model organisms such as Caenorhabditis elegans (nematode worm) and Danio rerio (zebrafish). This core facility function synergistically with the genomics core facility (Core-B), to identify genes that impact functions of probes in vivo, and with the microfabrication core facility (Core-D), to develop devices for imaging and chemical analysis. This integration will empower faculty to use chemical biology approaches to investigate biological problems. This core facility will provide access to highly qualified personnel with experience in synthetic organic chemistry, biochemistry, microscopy, and computational methods for optimization of biological properties of synthetic molecules. Core staff will facilitate prolse design, synthesis, optimization, conjugation, delivery, imaging, data acquisition, data analysis, and interpretation of digital images and video. Working with the core leader. Prof. Blake Peterson in the Department of Medicinal Chemistry at KU, whose research spans the chemistry/biology interface, investigators will gain access to novel fluorophores and delivery systems optimized for in vivo applications, fluorescent sensors of metal ions, pH, and other physiological processes, and fluorescent probes designed for imaging of tumors in vivo in model organisms. Computational support for the design of probes with suitable spectroscopic and pharmacokinetic properties, data analysis, data management, and data curation will be provided by Dr. Gerald Lushington, the Director of the Molecular Graphics and Modeling Laboratory at KU.
The specific aims of the SMP core are: (1) To design, synthesize, evaluate, and optimize novel fluorescent probes of physiology and pathology for in vitro bioassays and in vivo imaging applications;(2) To provide access to instrumentation for time-dependent visualization of fluorescent probes delivered by microinjection or feeding of model organisms;(3) To offer innovative cholesterylamine-based delivery systems for in vivo imaging applications.
C. elegans (nematode worm) and D. rerio (zebrafish) represent two of the best model organisms for understanding the biology of all animals. Because these animals can be easily manipulated and studied alive by fluorescence microscopy, novel fluorescent molecular probes optimized for in vivo imaging of normal physiology and pathology in these models represent powerful tools for elucidating mechanisms of disease. Molecular probes developed through this core facility are likely to have broad utility to a wide variety of investigators.
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