This proposal is a Recovery Act Competitive Revision as specified in notice number NOT-OD- 09-058, NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. The parent grant is R01 GM054403, IMP Dehydrogenase. IMP dehydrogenase (IMPDH) controls the entry of purines into the guanine nucleotide pool, thereby controlling proliferation and many other physiological processes. We have recently discovered that this enzyme associates with polyribosomes, suggesting that it also plays a role in the regulation of translation. The importance of this finding is underscored by the observation that polyribosome association is disrupted by mutations in IMPDH1 that cause hereditary blindness. This revision seeks additional funding to investigate a remarkable new finding: two novel IMPDH1 isoforms, generated by alternative mRNA splicing, were recently discovered in the retina. We find that these isoforms associate specifically with polyribosomes translating rhodopsin mRNA;disruption of the interaction between IMPDH1 and rhodopsin mRNA provides an attractive mechanism for disease. This revision investigates the interaction of IMPDH1 with rhodopsin polyribosomes. Characterization of this moonlighting function will define a new physiological role for this """"""""enzyme of consequence"""""""" in virtually every organism and provide important new insights into the poorly understood arena of translational control. Therefore the impact of this work will extend far beyond retinal diseases. The proposed experiments will characterize the retinal IMPDH1 isoforms, identify the protein domains and RNA sequence motif(s) that control the association with polyribosomes translating rhodopsin, which in turn will allow the identification of other target mRNAs and factors. This work will provide important new insights into a novel moonlighting function of this """"""""enzyme of consequence"""""""" for virtually every organism.
Retinitis pigmentosa (RP) is the most prevalent hereditary retinopathy, affecting approximately 1 in 4000 people. IMPDH1-mediated RP accounts of 3-4% casess. This work will demarcate a model for the molecular mechanism of IMPDH1-linked retinal disease and identify sequence motifs and/or protein factors that may be responsible for phenotypic heterogeneity of disease. Further, these motifs/factors will be new candidates for the 25% of hereditary retinal disease that is currently undefined.
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