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 调节脊椎间盘(IVD)的形成和发展的机制不是 很好理解。我们目前对静脉畸形形成的有限知识建立在遗传小鼠模型上， 但仍有很多东西需要学习。退行性腰椎间盘疾病(DDD)是慢性下腰痛的主要原因 (CLBP)，影响全球数百万人的流动性和生活质量，然而，没有治疗方法或 解药。更好地理解细胞和分子基础的形成、发育和维持 对健康IVD的研究将有助于测试关键发育分子在再生再生中的作用 静脉注射症。NIH共同基金数据集由Knokout Mouse表型计划(KOMP)生成，KOMP是 国际小鼠表型联盟(IMPC)是一个全基因组的小鼠基因敲除集合。这个 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- 在小鼠基因组中编码基因，并深入了解其在人类健康中的作用。一个标准化的 紧随其后的是21个研究中心，这些中心正在进行单基因敲除小鼠的研究 在两性中都有遗传和表型。我们这项工作的主要假设是，一个更好的 了解调节间盘(IVD，或Disk)发育和 维护，并可以提供对IVD病理的分子洞察力。之前我们报道过胸罩，一种 关键的发育调节因子也在IVDS的出生后髓核(NP)细胞中表达，并且 BRA的表达随着病理性IVD年龄的增长而下降。NP细胞是胚胎的后代 Notochord，我们之前的工作表明，出生后的NP继续作为信号中心发挥调节作用 通过SHH信号调节周围细胞的生长和分化。拟议研究的目标是 要充分利用NIH共同基金KOMP和GTEx门户数据集以及非CF数据集，如 用于筛选IVD发展所需的新基因的字符串数据库、OMIM和公开可用的GWAS数据集 和维护。我们将系统地对基因进行优先排序，以确定它们丢失对IVD的影响 使用IMPC生成和表征的单一KO击倒进行开发和维护，即 在杂合子或纯合子条件下能存活，有中轴性骨骼缺陷，与人类健康有关 利用我们的筛查渠道。拟议研究的完成将确定与IVD相关的新基因，以及 未来的机制研究可以检验与它们在IVD的形成、分化、 或者是健康维护。