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CGRP-CLR mediated regulation of bone healing

CGRP-CLR 介导的骨愈合调节

基本信息

批准号：
10659882
负责人：
IVO Kalajzic
金额：
$ 41.72万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-05 至 2028-02-29
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10659882
关键词：
Affect Binding Biology Biomechanics Bone Injury Bone callus Calcitonin Calcitonin Gene-Related Peptide Calcitonin-Gene Related Peptide Receptor Cell Differentiation process Cell Lineage Cells Chemicals Chondrocytes Chondrogenesis Chronic Clinical Complex Data Denervation Endothelial Cells Endothelium Exhibits FDA approved Fracture Future Genes Genetic Transcription Genomics Growth Factor Histology Impaired healing Impairment Intervention Lead Ligands Long-Term Effects Mechanics Mediating Medical Care Costs Mesenchymal Mesenchymal Stem Cells Migraine Modeling Molecular Molecular Target Mus Neuropeptides Osteoblasts Osteogenesis Outcome Pathogenesis Peptide Signal Sequences Periosteal Cell Periosteum Pharmaceutical Preparations Phenotype Population Positioning Attribute Prevention Preventive treatment Process Proteins Quality of life RAMP1 RAMP2 RAMP3 Receptor Signaling Regulation Risk Role Sensory Sensory Receptors Signal Transduction Site Testing Therapeutic Tissues Undifferentiated Vascularization adrenomedullin afferent nerve aggrecan antagonist bone bone fracture repair bone healing bone turnover calcitonin receptor-like receptor healing improved in vivo in vivo evaluation inducible Cre inhibitor migraine treatment nerve supply neurotransmission novel pain signal promoter receptor response response to injury stem cell proliferation stem cells targeted treatment tomography translational approach

项目摘要

Periosteum, a primary site of the fracture healing response, is highly vascularized and densely innervated. Studies on bone fracture have primarily focused on the role of growth factors and vascularization in the healing process, but we postulate that sensory nerve signals are a critical part of the regulatory mechanism that initiate the stem/progenitor cell responses required for fracture callus formation. A number of lines of evidence point to sensory innervation, or signals associated with sensory nerves as promoters of bone accrual and healing. For example, fracture healing is impaired following chemical sensory denervation, but the sensory nerve-derived signals that promote healing as not yet defined. We hypothesize that damage to sensory nerves in the periosteum orchestrates the bone-healing cascade through calcitonin gene-related peptide (CGRP) – calcitonin like receptor (CLR) signaling. This is important given that multiple CGRP inhibitors were recently approved by the FDA for prevention and treatment of migraines. In Aim 1 we will evaluate the effects of CGRP inhibitors on bone healing. Given that CGRP plays a role in bone turnover and potentially healing, it is important to understand the impact of CGRP inhibition on fracture healing. In the Aim 2, we will determine which cell lineage or lineages responsive to CGRP signals during healing using targeted deletion of the CLR receptor. CLR deletion in early fracture healing will be targeted to the following lineages using inducible Cre’s: MPCs (αSMA-CreER), chondrocyte (Acan)-CreER, osteoblasts using Col2.3CreER and in endothelial (Cdh5-CreER) during fracture healing. The effects on callus formation and strength, as well as differentiation in the callus will be determined. We will examine cellular mechanisms of CGRP/CLR action utilizing in vivo approaches to study MPC expansion, differentiation and vascularization. We propose to dissect CLR signaling by distinguishing effects of the ligands. The main ligands are CGRP and Adrenomedullin that act via CLR and RAMP, of which CLR-RAMP1 is main complex for CGRP signaling while CLR-RAMP2 and RAMP3 is responsible for ADM signal activation. In Aim 3 we will evaluate effects of ADM deletion in mesenchymal population using ADMfl/fl mice. We will also define downstream signaling mechanism of CLR deletion in MSCs and endothelial cells using 10x genomics. Our study will also provide critical information on the effects that newly approved inhibitors of CGRP signaling exhibit on bone healing and what cellular mechanisms affect healing via CLR receptor Finally, testing approaches to modulate CGRP/CLR sensory singling may lead to a therapeutic strategy to enhance bone healing.

骨膜是骨折愈合反应的主要部位，血管丰富且密度大