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The Discovery of Human Peptide Encoding Genes

人类肽编码基因的发现

基本信息

批准号：
10523012
负责人：
Clodagh O'Shea
金额：
$ 48.31万
依托单位：
SALK INSTITUTE FOR BIOLOGICAL STUDIES
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-21 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10523012
关键词：
Adopted Agonist Algorithms Amino Acid Sequence Amino Acids Antibodies Area Base Pairing Biochemical Biological Biological Process Biological Products Biology Catalogs Cell Line Cells Code DNA DNA Repair DNA Sequence Disease Ecosystem Essential Genes Foundations G-Protein-Coupled Receptors Gene Family Generations Genes Genetically Engineered Mouse Genome Goals Human Human Genome Human Genome Project Insulin Knowledge Learning Length Link Malignant Neoplasms Medicine Messenger RNA Mitochondria Molecular Biology Molecular Medicine Open Reading Frames Peptides Physiology Protein Databases Proteins Proteolysis Proteomics Protocols documentation RNA Sequences Reagent Retinal blind spot Ribosomes Role Scientist Structure Syndrome Therapeutic Tissues Translating Translational Regulation Translations Work biological adaptation to stress cis acting element drug development endoplasmic reticulum stress frontier gene discovery genomic platform human disease human genome sequencing improved in vivo mammalian genome new therapeutic target novel receptor small molecule small molecule inhibitor therapeutic development

项目摘要

ABSTRACT Understanding the information contained within the human genome has been a goal of molecular biology and medicine since the identification of DNA. The Human Genome Project cataloged all the protein-coding genes embedded within the genome, but gene-finding algorithms had a blind spot for protein-coding small open reading frames (smORFs). Technological advances over the last decade have led to the discovery of thousands of smORFs in the human genome that encode peptides or small proteins (median length 30 amino acids) collectively referred to as microproteins. The discovery of thousands of previously unknown proteins in the human genome is an exciting opportunity in molecular biology that promises to improve scientific understanding and the ability to discover and develop new medicines. This proposal seeks to answer important questions that have emerged regarding microproteins, including whether microproteins from polycistronic genes are functional (Aim 1), whether biologically active secreted microproteins exist (Aim 2), and, lastly, whether it is possible to use knowledge about the structure and mechanism of microproteins to develop small-molecule probes that can regulate their actives in cells (Aim 3). These questions will be tackled using approaches and reagents developed over the last decade. For example, optimized robust protocols are now available for investigating microprotein-protein interactions together with necessary reagents including antibodies, cell lines, and genetically engineered mice to study these unique genes. This proposal will reveal new functions for microproteins in cells and tissues, identify biologically active secreted microproteins, and identify small molecule probes of microprotein biology. These efforts will increase understanding of the roles of smORFs and microproteins in mammalian genomes and identify secreted microproteins and small molecules that provide a template for converting these foundational discoveries into medicines.

抽象的了解人类基因组中包含的信息一直是分子生物学的目标自从 DNA 鉴定以来，医学一直在发展。人类基因组计划对所有蛋白质编码基因进行了编目嵌入基因组中，但基因查找算法在蛋白质编码小开放阅读方面存在盲点框架（smORF）。过去十年的技术进步已导致数以千计的发现人类基因组中编码肽或小蛋白的 smORF（中位长度 30 个氨基酸）统称为微生物蛋白质。发现了数千种以前未知的蛋白质人类基因组是分子生物学中一个令人兴奋的机会，有望提高科学理解以及发现和开发新药的能力。该提案旨在回答有关微生物蛋白质的重要问题，包括来自多顺反子基因的微生物蛋白是否具有功能（目标 1），是否具有生物活性微生物蛋白的存在（目标 2），最后，是否可以利用有关其结构和结构的知识研究微生物蛋白的机制，开发可调节其在细胞中活性的小分子探针（目标 3）。这些问题将使用过去十年开发的方法和试剂来解决。例如，优化的稳健协议现在可用于研究微生物蛋白质-蛋白质相互作用研究这些独特的必要试剂，包括抗体、细胞系和基因工程小鼠基因。该提案将揭示细胞和组织中微生物蛋白的新功能，识别生物活性分泌的微生物蛋白，并鉴定微生物蛋白生物学的小分子探针。这些努力将增进对 smORF 和微生物蛋白在哺乳动物中的作用的理解基因组并识别分泌的微生物蛋白和小分子，为转化这些提供模板药物的基础性发现。