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.

项目概要/摘要 调节脊柱椎间盘（IVD）形成和发育的机制并不 很好理解。我们目前对 IVD 形成的有限了解是建立在遗传小鼠模型的基础上的， 但还有很多东西需要学习。退行性椎间盘疾病 (DDD) 是慢性腰痛的主要原因 （cLBP），影响着全世界数百万人的流动性和生活质量，然而，没有治疗方法或 治愈。更好地了解形成、发育和维持的细胞和分子基础 健康 IVD 的研究将有助于测试关键发育分子在细胞再生和年轻化中的作用 体外诊断设备。 NIH 共同基金数据集由淘汰小鼠表型计划 (KOMP) 生成，该计划是 国际小鼠表型联盟 (IMPC) 是一个全基因组小鼠基因敲除集合。这 KOMP 和 IMPC 的目标是通过敲除每一种蛋白质来生成哺乳动物基因功能的目录 小鼠基因组中的编码基因，并深入表型以了解其在人类健康中的作用。一个标准化的 表型分析管道紧随其后的是 21 个研究中心，这些中心正在研究单基因敲除小鼠 在两性中均产生并表现型。我们这项工作的总体假设是更好的 了解调节椎间盘（IVD 或椎间盘）发育的基因及其网络， 维护，并可以提供 IVD 病理学的分子见解。之前我们报道过 BRA， IVD 的出生后髓核 (NP) 细胞也表达关键的发育调节因子 BRA 的表达随着病理性 IVD 老化而下降。 NP细胞是胚胎细胞的后代 脊索，我们之前的工作表明出生后 NP 继续充当信号中心并调节 通过 SHH 信号传导周围细胞的生长和分化。拟议研究的目标是 充分利用 NIH 共同基金 KOMP 和 GTEx 门户数据集以及非 CF 数据集，例如 STRING-db、OMIM 和公开可用的 GWAS 数据集，用于筛选 IVD 开发所需的新基因 和维护。我们将系统地对基因进行优先排序，以表征其丢失对 IVD 的影响 使用 IMPC 生成和表征的单 KO 敲除进行开发和维护，这些 在杂合或纯合条件下可存活，具有轴向骨骼缺陷并且与人类健康相关 使用我们的筛选管道。完成拟议的研究将鉴定与 IVD 相关的新基因，并且 未来的机制研究可以检验与其在 IVD 形成、分化、 或健康维护。