IMP Dehydrogenase

描述（由申请人提供）：该提案是一项恢复法案竞争性修订，如通知号no - od - 09-058所述，NIH宣布恢复法案基金可用于竞争性修订申请。母基金为R01 GM054403， IMP Dehydrogenase。IMP脱氢酶（IMPDH）控制嘌呤进入鸟嘌呤核苷酸库，从而控制增殖和许多其他生理过程。我们最近发现这种酶与多核糖体结合，表明它也在翻译调节中起作用。这一发现的重要性被观察到，多核糖体关联被导致遗传性失明的IMPDH1突变破坏。这一修订寻求额外的资金来研究一个显着的新发现：最近在视网膜中发现了两种新的IMPDH1亚型，它们是由替代mRNA剪接产生的。我们发现这些异构体与翻译视紫红质mRNA的多核糖体特异性相关；破坏IMPDH1和视紫红质mRNA之间的相互作用为疾病提供了一个有吸引力的机制。本修订版研究了IMPDH1与视紫红质多核糖体的相互作用。这种兼职功能的特征将定义这种“重要酶”在几乎所有生物体中的新生理作用，并为知之甚少的翻译控制领域提供重要的新见解。因此，这项工作的影响将远远超出视网膜疾病。所提出的实验将表征视网膜IMPDH1亚型，鉴定控制与多核糖体翻译视紫红质的关联的蛋白质结构域和RNA序列基序，这反过来将允许鉴定其他靶mrna和因子。这项工作将为这种“重要酶”的一种新的兼职功能提供重要的新见解，这种功能几乎适用于所有生物体。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.