Identifying regulatory uORFs as a targetable axis for hereditary disease

识别调节性 uORF 作为遗传性疾病的靶向轴

基本信息

批准号：
10709564
负责人：
Yoseph Barash
金额：
$ 40.4万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-23 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10709564
关键词：
5&apos Untranslated Regions Affect Animal Model Animals Antisense Oligonucleotides BMPR2 gene Back Biological Assay Biology Cell Culture Techniques Cells Code Communities Computer Models Coupled Data Data Set Databases Disease Dose Enzyme-Linked Immunosorbent Assay Evolution Exhibits Future Gene Proteins Genes Genetic Genetic Databases Genetic Diseases Genomics Goals Grant Hereditary Disease Heritability Human Initiator Codon Intervention Knowledge Luciferases Maps Measures Messenger RNA Modeling Molecular Biology Mus Mutate Open Reading Frames Output Pathway interactions Patients Peptides Phenotype Proteins Publishing Pulmonary artery structure RNA RNA Processing Regulatory Element Reporter Resources Rest Role Signal Pathway Terminator Codon Testing Therapeutic Therapeutic Intervention Translations Validation Variant Work biobank clinically relevant computational pipelines design disease phenotype dosage experimental study genetic variant improved in vivo in vivo evaluation mouse model novel preservation protein expression pulmonary arterial hypertension targeted treatment translational approach translational potential user-friendly web-based tool

项目摘要

Abstract The aim of this grant is to identify, validate, then target for therapeutic intervention, regulatory elements within the 5’ untranslated regions (UTR) of protein coding genes, known as upstream open reading frames (uORFs). In so doing, we aim to modulate the protein output from selected genes, offering a novel, translational approach with broad potential, that we will first test in the context of animal models of hereditary diseases. To achieve the goals of our integrative MultiPI R01, we will leverage the expertise of both our labs spanning computational modeling, genomics, genetics, RNA biology, molecular biology, and animal work. In Aim 1 we will combine large genomic and genetic datasets including gnomAD, the PennMedicine BioBank, and the UKBioBank to systematically identify functional uORFs and prioritize those for validation. The resulting database of human uORFs will be made publicly available and widely accessible as a user-friendly web-tool. Predicted regulatory uORFs suggested by the Aim 1 pipeline will be fed into the experimental Aims 2 and 3. In Aim 2 we will validate the high-priority uORF targets using luciferase assays and in Aim 3 we will test the modulation of these uORFs as a potential for therapeutic intervention. The results of Aims 2 and 3 will be fed back to the pipeline of Aim1 to improve prioritization of future uORFs. Overall, we expect the resources and discoveries made by this grant to shed light on the functional role of uORF and offer therapeutic avenues for several hereditary diseases.

抽象的这笔赠款的目的是识别，验证，然后针对热干预，监管元素蛋白质编码基因的5'未翻译区域（UTR），称为上游开放式阅读框（UORFS）。这样，我们旨在调节选定基因的蛋白质输出，提供一种新颖的翻译具有广泛潜力的方法，我们将首先在遗传性疾病的动物模型中进行测试。到实现我们集成的Multipi R01的目标，我们将利用两个实验室的专业知识计算建模，基因组学，遗传学，RNA生物学，分子生物学和动物工作。在目标1中我们将结合包括GNOMAD，Pennmedicine Biobank和的大型基因组和遗传数据集结合 UKBiobank系统地识别功能性UORF并确定验证的功能。结果人类UORF的数据库将被公开可用，并以用户友好的网络工具的范围广泛访问。 AIM 1管道提出的预测调节UORF将被送入实验目标2和3。 AIM 2我们将使用荧光素酶测定法验证高优先级UORF目标，在AIM 3中，我们将测试调节这些UORF是治疗干预的潜力。目标2和3的结果将被喂养回到AIM1的渠道，以改善未来UORF的优先级。总体而言，我们期望资源和这笔赠款的发现阐明了UORF的功能作用，并提供了治疗途径几种世袭疾病。