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