? This supplemental application requests funding for equipment to establish a Core Module in Functional Genomics, which has three interrelated components that will be used extensively by the PJIs and related research projects. The three components of the Functional Genomics Module are: 1) A facility that will be used to test gene function in genetically modified mice. We will create a state-of-the-art mouse genetics facility, which will mainly support the manipulation of the mouse genome by targeted mutagenesis in mouse embryonic stem cells. This facility will allow us to generate animal models of human diseases and pathology through precise genomic modifications in mouse embryonic stem cells. 2) An in vitro facility for reverse genetics using RNA interference in cell culture. RNAi, the introduction of sequence-specific double-stranded small inhibiting RNAs (siRNAs), has become a powerful tool to knock down gene expression in isolated cells, siRNAs can be introduced into retinal neurons grown in a chemically defined environment to study the function of numerous genes. The inhibition of the expression of endogenous and transfected genes using in vitro systems can be evaluated free from the homeostatic influence of the whole organism. 3) An in vivo facility for reverse genetics using RNA interference in animal models. The therapeutic potential of iRNA will be investigated by long-term expression of the siRNA molecules in the terminally differentiated cells of the intact retina. Funds are requested for equipment only; no funds are requested for A&R. Successful implementation of this Functional Genomics Module will shorten the time for submission of first-time R01 applications by our 5 COBRE-funded promising junior investigators, and expand the research horizons for 15 other vision researchers, module directors, and/or COBRE mentors on our campus. ? ?
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