权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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.

摘要该基金的目的是识别、验证，然后针对治疗干预，蛋白质编码基因的5'非翻译区（UTR），称为上游开放阅读框（uORF）。在这样做的过程中，我们的目标是调节选定基因的蛋白质输出，提供一种新的，翻译的，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。到为了实现我们的综合MultiPI R01的目标，我们将利用我们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、分子生物学和动物研究。在目标1中，将联合收割机结合大型基因组和遗传数据集，包括gnomAD、宾夕法尼亚医学生物银行和 UKBioBank将系统地识别功能性uORF，并优先考虑验证。所得人类uORF数据库将作为一个用户友好的网络工具向公众开放和广泛访问。目标1管道建议的预测调控uORF将被输入实验目标2和3。在目标2中，我们将使用荧光素酶测定来验证高优先级uORF靶标，并且在目标3中，我们将测试高优先级uORF靶标。这些uORF的调节作为治疗干预的潜力。目标2和目标3的结果将在回到Aim 1的管道，以提高未来uORF的优先级。总的来说，我们希望资源和这项资助的发现揭示了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