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，然后针对治疗干预、监管要素蛋白质编码基因的 5' 非翻译区 (UTR)，称为上游开放阅读框 (uORF)。在此过程中，我们的目标是调节选定基因的蛋白质输出，提供一种新颖的翻译这种方法具有广泛的潜力，我们将首先在遗传性疾病的动物模型中进行测试。为了实现我们综合 MultiPI R01 的目标，我们将利用我们两个实验室的专业知识在目标 1 中，我们涉及计算建模、基因组学、遗传学、RNA 生物学、分子生物学和动物工作。将结合大型基因组和遗传数据集，包括 gnomAD、PennMedicine BioBank 和 UKBioBank 以某种方式识别功能性 uORF 并优先进行验证。人类 uORF 数据库将作为用户友好的网络工具公开并广泛访问。目标 1 管道建议的预测监管 uORF 将被输入到实验目标 2 和 3 中。目标 2 我们将使用荧光素酶测定验证高优先级 uORF 靶标，在目标 3 中我们将测试这些 uORF 的调节作为治疗干预的潜力将被提供给目标 2 和 3 的结果。回到 Aim1 的流程，以提高未来 uORF 的优先级。总体而言，我们期望获得资源和支持。该资助的发现揭示了 uORF 的功能作用并为以下疾病提供了治疗途径：几种遗传性疾病。