Role of the FAAH-OUT locus in cutaneous wound healing

FAAH-OUT 基因座在皮肤伤口愈合中的作用

• 批准号: 10334272
• 负责人: Bryan Sun
• 金额: $ 50.66万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10334272
• 关键词: Acute; Aldehydes; Alleles; Binding; Biological Assay; Biological Process; Cells; Chromatin; Cicatrix; Clinical; DNA; Dermatology; Enhancers; Epithelial; Fatty Acids; Fibroblasts; Foundations; Genes; Genetic; Genetic Transcription; Genetic study; Genome engineering; Genotype; Goals; Grant; Human; Hydrolase; In Situ Hybridization; Individual; Injury; Knockout Mice; Laboratories; Lead; Learning; Link; Lipids; Medical; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Conformation; Molecular Genetics; Mutagenesis; Names; Organoids; Outcome; Pathway interactions; Patients; Phenotype; Physicians; Process; Property; Proteins; Regulatory Element; Research; Research Personnel; Role; Skin; Skin Tissue; Skin injury; Skin repair; Skin wound healing; Study Subject; Testing; Tissues; United States; Untranslated RNA; Woman; Wound healing therapy; aging population; base; chronic wound; experience; experimental study; gain of function; genome sequencing; genomic locus; improved; innovation; insight; keratinocyte; loss of function; migration; new therapeutic target; novel; novel therapeutics; repair model; skin regeneration; skin wound; skin xenograft; targeted treatment; tissue repair; transcriptomics; wound; wound healing; wound treatment

RESEARCH SUMMARY The proposal will study the unusual phenotype of a 69-year-old woman who displays exceptionally accelerated skin wound healing with minimal scarring. Genome sequencing revealed that her phenotype is caused by an ~8 kb deletion downstream of the fatty acid aldehyde hydrolase (FAAH) gene that results in the loss of a long noncoding RNA (lncRNA) gene named FAAH OUT. The goal of this proposal is to understand how the FAAH OUT deletion results in accelerated wound healing. In the United States, the annual medical burden of chronic wounds exceeds $25 billion and continues to rise with the aging population. There is a critical need to improve understanding of the biological processes underlying skin wound healing and to innovate new therapies. In the first aim, we will study normal and wounded skin tissue from the study subject using spatial transcriptomics, in situ hybridization, and xenograft skin repair models to understand how the FAAH OUT locus regulates wound healing. In the second aim, we will elucidate the FAAH OUT genetic interactome to gain insight to its molecular mechanisms. By studying a rare genetic allele of an individual with markedly enhanced wound healing, this proposal aims to generate novel insight to the role of lncRNAs in wound repair and discover new human-validated targets to treat cutaneous wounds.

研究概要 该提案将研究一名表现异常的 69 岁女性的不寻常表型 加速皮肤伤口愈合，最小化疤痕。基因组测序显示她 表型是由脂肪酸醛水解酶下游约 8 kb 的缺失引起的 (FAAH) 基因导致名为 FAAH OUT 的长非编码 RNA (lncRNA) 基因的丢失。 该提案的目标是了解 FAAH OUT 删除如​​何导致加速 伤口愈合。在美国，慢性伤口每年的医疗负担超过25美元 亿，并随着人口老龄化而持续增长。迫切需要改进 了解皮肤伤口愈合的生物过程并创新 疗法。第一个目标是研究研究对象的正常和受伤皮肤组织 使用空间转录组学、原位杂交和异种移植皮肤修复模型来了解 FAAH OUT 基因座如何调节伤口愈合。在第二个目标中，我们将阐明FAAH OUT 遗传相互作用组以深入了解其分子机制。通过研究一种罕见的基因 伤口愈合显着增强的个体的等位基因，该提案旨在产生 对 lncRNA 在伤口修复中的作用有了新的见解，并发现了经过人类验证的新靶点 治疗皮肤伤口。