Admin Supplement: Role of Shh/Brachyury axis in the maintenance of the postnatal intervertebral disc

管理补充：Shh/Brachyury 轴在产后椎间盘维护中的作用

• 批准号: 10879520
• 负责人: Chitra L Dahia
• 金额: $ 26.85万
• 依托单位: HOSPITAL FOR SPECIAL SURGERY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10879520
• 关键词: Acceleration; Affect; Age; Aging; Atlases; Brachyury protein; Catalogs; Cells; Chronic low back pain; Code; Collection; Data Set; Databases; Defect; Development; Differentiation and Growth; Ecosystem; Embryo; Embryonic Structures; Funding; Future; Genes; Genetic; Genotype-Tissue Expression Project; Goals; Growth; Health; Hereditary Disease; Heterozygote; Histologic; Human; Injury; International; Intervertebral disc structure; Knock-out; Knockout Mice; Knowledge; Learning; Ligands; Maintenance; Molecular; Morphology; Mus; Natural regeneration; Online Mendelian Inheritance In Man; Pain; Pathologic; Pathology; Persons; Phenotype; Population; Process; Proteins; Publishing; Quality of life; Rejuvenation; Reporting; Research; Resources; Role; SHH gene; Signal Transduction; Skeleton; Standardization; Structure; Testing; Therapeutic; United States National Institutes of Health; Vertebral column; Work; age related; chronic back pain; data portal; effective therapy; experimental study; gastrulation; gene function; genome wide association study; genome-wide; insight; intervertebral disk degeneration; knockout gene; mouse genome; mouse model; mutant; neonatal mice; notochord; novel; nucleus pulposus; parent grant; pathological aging; postnatal; postnatal development; programs; protein protein interaction; screening; sex; skeletal; smoothened signaling pathway; targeted treatment; transcription factor; transcriptome sequencing

PROJECT SUMMARY/ ABSTRACT Mechanisms that regulate the formation and development of the intervertebral discs (IVDs) of the spine are not well understood. Our current limited knowledge of the formation of the IVDs is built on genetic mouse models, but much remains to be learned. Degenerative disc disease (DDD) is a leading cause of chronic low back pain (cLBP), affecting the mobility and quality of life of millions of people worldwide, however, with no therapeutics or cure. A better understanding of the cellular and molecular basis of the formation, development, and maintenance of healthy IVD will help test the role of key developmental molecules in the regeneration of rejuvenation of the IVDs. NIH Common Fund datasets generated by the Knockout Mouse Phenotyping Program (KOMP), a part of the International Mouse Phenotyping Consortium (IMPC), is a genome-wide collection of mouse knockouts. The goal of KOMP and IMPC is to generate a catalog of mammalian gene function, by knocking out every protein- coding gene in the mouse genome, and deeply phenotype to understand its role in human health. A standardized phenotyping pipeline is followed by the 21 research centers where the single-gene knockout mice are being generated and phenotyped in both sexes. Our overarching hypothesis underlying this work is that a better understanding of the genes and their network that regulate intervertebral disc (IVD, or disc) development and maintenance, and can provide molecular insights into IVD pathologies. Previously we reported that BRA, a critical developmental regulator is also expressed by postnatal nucleus pulposus (NP) cells of the IVDs and that the expression of BRA declines with pathological IVD aging. NP cells are descendants of the embryonic notochord, and our previous work showed the postnatal NP continues to act as the signaling center and regulate the growth and differentiation of surrounding cells via SHH signaling. The goal of the proposed study is to substantially leverage NIH Common Fund KOMP and GTEx portal datasets along with non-CF datasets like STRING-db, OMIM, and publicly available GWAS datasets to screen novel genes required for IVD development and maintenance. We will systematically prioritize genes to characterize the effect of their loss on IVD development and maintenance using the single-KO knockouts generated and characterized by IMPC, that are viable in heterozygous or homozygous conditions, have axial skeleton defects and are relevant to human health using our screening pipeline. Completion of the proposed study will identify novel genes relevant to IVD, and future mechanistic studies can test the hypothesis related to their specific roles in IVD formation, differentiation, or health maintenance.

项目摘要/摘要 调节脊柱椎间盘（IVD）的形成和发展的机制不是 理解。我们目前对IVD形成的有限了解是建立在遗传小鼠模型上的， 但是还有很多要学习的东西。退化性椎间盘疾病（DDD）是慢性下背痛的主要原因 （CLBP），影响全球数百万人的流动性和生活质量，但是没有治疗学或 治愈。更好地理解形成，发展和维护的细胞和分子基础 健康的IVD将有助于测试关键发育分子在再生中的作用 IVD。 NIH公共基金数据集由淘汰鼠标表型计划（KOMP）生成 国际小鼠表型联盟（IMPC）是全基因组敲除的集合。这 Komp和IMPC的目标是通过淘汰所有蛋白质来产生哺乳动物基因功能的目录 在小鼠基因组中编码基因，并深刻了解其在人类健康中的作用。标准化 表型管道之后是21个研究中心，其中单基因敲除小鼠正在 在两个性别中产生和表型。这项工作的基础我们的总体假设是更好 了解调节椎间盘（IVD或椎间盘）开发的基因及其网络以及 维持，可以为IVD病理提供分子见解。以前我们报道了胸罩 关键发育调节剂还通过IVD的产后核（NP）细胞表达 胸罩的表达随着病理IVD衰老而下降。 NP细胞是胚胎的后代 Notochord，我们以前的工作表明，产后NP继续充当信号中心并调节 通过SHH信号传导的周围细胞的生长和分化。拟议的研究的目的是 实质上利用NIH Common Fund Fund Komp和GTEX Portal数据集以及非CF数据集 String-DB，OMIM和公开可用的GWAS数据集，以筛选IVD开发所需的新颖基因 和维护。我们将系统地确定基因以表征其损失对IVD的影响 使用IMPC产生和特征的单ko敲除开发和维护，即 在杂合或纯合条件下可行，具有轴向骨骼缺陷，与人类健康有关 使用我们的筛选管道。拟议研究的完成将确定与IVD相关的新基因，并且 未来的机械研究可以检验与它们在IVD形成，分化， 或健康维护。