IMP Dehydrogenase

IMP脱氢酶

• 批准号: 7835359
• 负责人: Lizbeth K. Hedstrom
• 金额: $ 27.85万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7835359
• 关键词: Accounting; Address; Affect; Antineoplastic Agents; Antiviral Agents; C-terminal; Disease; Enzymes; Funding; Goals; Guanine Nucleotides; Heterogeneity; IMP Dehydrogenase; IMPDH1 gene; Immunosuppressive Agents; Inherited; Inosine Monophosphate; Link; Mediating; Messenger RNA; Molecular Models; Mutation; Organism; Oxidoreductase; Physiological; Physiological Processes; Play; Polyribosomes; Protein Isoforms; Proteins; Purines; RNA Sequences; RNA Splicing; Reaction; Recovery; Regulation; Retina; Retinal; Retinal Diseases; Retinitis Pigmentosa; Rhodopsin; Role; Specific qualifier value; Tertiary Protein Structure; Translating; Translations; United States National Institutes of Health; Work; hereditary blindness; insight; molecular modeling; novel; oxidation; parent grant; public health relevance; purine; research study; xanthosine monophosphate

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.

描述（由申请人提供）：本提案是《恢复法》竞争性修订，如通知号NOT-OD- 09-058所述，NIH宣布《恢复法》资金可用于竞争性修订申请。母授权是R 01 GM 054403，IMP脱氢酶。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，这种酶与多聚核糖体，这表明它也在翻译的调节中发挥作用。这一发现的重要性是强调了观察，多核糖体协会被破坏的突变IMPDH 1，导致遗传性失明。这次修订寻求额外的资金来研究一个引人注目的新发现：最近在视网膜中发现了两种新的IMPDH 1亚型，由mRNA剪接产生。我们发现，这些异构体与翻译视紫红质mRNA的多聚核糖体特异性相关; IMPDH 1和视紫红质mRNA之间的相互作用的破坏提供了一个有吸引力的疾病机制。这次修订调查IMPDH 1与视紫红质多聚核糖体的相互作用。这种兼职功能的特性将定义一个新的生理作用，这种“酶的后果”，在几乎每一个有机体，并提供重要的新见解，了解很少的竞技场的翻译控制。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IMPDH 1亚型，鉴定控制与翻译视紫红质的多聚核糖体缔合的蛋白质结构域和RNA序列基序，这反过来将允许鉴定其他靶mRNA和因子。这项工作将提供重要的新的见解，这种“酶的后果”的一种新的兼职功能，几乎每一个有机体。 视网膜色素变性（RP）是最常见的遗传性视网膜病变，大约每4000人中就有1人患病。IMPDH 1介导的RP占3-4%的病例。这项工作将划定IMPDH 1相关视网膜疾病的分子机制的模型，并确定可能导致疾病表型异质性的序列基序和/或蛋白质因子。此外，这些基序/因子将成为目前尚未确定的25%遗传性视网膜疾病的新候选者。