Identification of osteoclast endocrine and paracrine communications by systems genetics approaches

通过系统遗传学方法鉴定破骨细胞内分泌和旁分泌通讯

基本信息

批准号：
10716388
负责人：
Marcus Michael Seldin
金额：
$ 33.85万
依托单位：
SOUTHERN CALIFORNIA INST FOR RES/EDUC
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：
2023-09-20 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10716388
关键词：
Accounting Adult Affect Albers-Schonberg disease American Animal Model Bioinformatics Biology Bone Marrow Bone Resorption Bone remodeling Cell Culture Techniques Cell Lineage Clinical Coculture Techniques Code Collection Communication Complex Consumption Coupled Coupling Data Set Disease Endocrine Endocrine Glands Ensure Exhibits Fracture Genes Genetic Genome Growth Hereditary Disease Homeostasis Hormones Human Hybrids In Vitro Inbred Strains Mice Individual Inflammatory Knowledge LIF gene Mass Spectrum Analysis Measures Metabolic Modeling Multiomic Data Mus Mutation Organ Organism Osteoblasts Osteocalcin Osteoclasts Osteocytes Osteogenesis Osteopenia Osteoporosis Paracrine Communication Pathologic Physiological Physiology Play Population Predisposition Process Protein Secretion Proteins Proteomics Public Health RNA Reporting Research Rheumatoid Arthritis Role Skeleton System Techniques Testing Time Tissues Transcript Validation Variant Work arthropathies bone bone fracture repair bone health bone loss bone mass cell type cost genetic approach genome sequencing human disease in vivo innovation loss of function model organism multiple omics new therapeutic target next generation novel osteoclastogenesis paracrine platelet-derived growth factor BB secretory protein skeletal disorder tool trait transcriptome sequencing whole genome

项目摘要

Bone resorption by osteoclasts plays a pivotal role in skeleton growth, homeostasis, and fracture repair. In adults, bone health is ensured by bone remodeling in which bone resorption is coupled and balanced by bone formation from osteoblasts. Therefore, the number and activities of osteoclasts are tightly regulated by systemic hormones and paracrine factors in bone marrow microenvironment. Meanwhile, bone itself is increasingly recognized as an endocrine organ which can modulate functions of other organs in whole-body physiology. While the systemic functions of endocrine factors derived from osteoblasts and osteocytes such as FGF23 and osteocalcin have been well established, the endocrine functions of osteoclast secreted proteins remain to be uncovered. To identify and functionally annotate endocrine and paracrine circuits, we have developed a novel systems genetic approach, termed Quantitative Endocrine Network Interaction Estimation (QENIE), that utilizes natural variation in transcript levels across tissues in multiple ‘omics’ datasets to predict modes of endocrine communication. Applying this approach to datasets in the hybrid mouse diversity panel (HMDP), a collection of approximately 100 inbred strains of mice exhibiting substantial diversity of most clinical traits relevant to human diseases, we have unraveled many known endocrine interactions as well as several novel tissue-tissue circuits. In the preliminary study leading to this proposal, we have quantitatively measured the levels of proteins and RNAs in precursor and mature osteoclasts by mass-spectrometry based proteomic and bulk RNA-seq. Hundreds of secreted proteins in osteoclast lineage cells have been identified by these ‘omics’ studies. While several osteoclast-derived coupling factors known to stimulate osteogenesis during bone remodeling are in the list of osteoclast secreted proteins, the endocrine and paracrine functions of most of these newly identified osteoclast secretory proteins are unknown. Based on our work and reports by others, we hypothesize that the endocrine and paracrine communications of osteoclasts play an important role in whole body and bone homeostasis under physiological and pathological conditions. To test our hypothesis, we will identify novel endocrine and paracrine circuits of osteoclast lineage cells by the system genetics bioinformatic framework QENIE (Aim 1) and experimentally validate and functionally assess these osteoclast-derived factors by in vitro cell culture and co-culture models (Aim 2). Successful accomplishment of the proposed work in this application will formulate new hypotheses to be tested using in vivo animal models and in human populations. The findings from this project will not only greatly advance our knowledge in osteoclast biology but also uncover new therapeutic targets to treat bone loss in bone and other organ diseases.

破骨细胞的骨骼分辨率在骨骼生长，稳态和断裂修复中起关键作用。在成人，骨骼健康可以通过骨头改造来确保骨骼分辨率与骨骼耦合并平衡成骨细胞的形成。因此，破骨细胞的数量和活动受到全身性的严格调节骨髓微环境中的骑马和旁分泌因子。平均虽然骨骼本身越来越多被公认为是内分泌器官，可以调节其他器官在全身生理学中的功能。而源自成骨细胞和骨细胞（例如FGF23和）的内分泌因子的全身功能骨钙素已经建立得很好，破骨细胞分泌蛋白的内分泌功能仍然是裸露。为了识别和功能注释内分泌和旁分泌电路，我们开发了一种新颖系统遗传方法，称为定量内分泌网络相互作用估计（Qenie），该方法利用多个“ OMICS”数据集中组织跨组织的自然变化，以预测内分泌的模式沟通。将此方法应用于混合鼠标多样性面板（HMDP）中的数据集，该方法的集合大约100个与人类相关的大多数临床特征表现出很大多样性的小鼠菌株疾病，我们揭示了许多已知的内分泌相互作用以及几个新型的组织 - 组织电路。在导致该提案的初步研究中，我们已经定量测量了蛋白质的水平和基于质谱的蛋白质组学和块状RNA-seq，前体和成熟破骨细胞中的RNA。这些“ OMICS”研究已经确定了破骨细胞谱系细胞中数百种分泌的蛋白质。尽管在骨重塑过程中已知刺激成骨的几个破骨细胞衍生的耦合因子破骨细胞分泌蛋白的列表，大多数新鉴定的大多数内分泌和旁分泌功能破骨细胞秘书蛋白是未知的。根据我们的工作和其他报告，我们假设破骨细胞的内分泌和旁分泌通讯在整个身体和骨骼中起重要作用身体和病理状况下的稳态。为了检验我们的假设，我们将确定新颖系统遗传学生物信息学框架的破骨细胞谱系细胞的内分泌和旁分泌电路 Qenie（AIM 1）并通过体外验证并在功能上验证这些破骨细胞的因素细胞培养和共培养模型（AIM 2）。在本申请中成功实现了拟议的工作将制定新的假设，以使用体内动物模型和人类种群进行测试。发现从这个项目中，我们不仅会促进我们在破骨细胞生物学方面的知识，而且还会发现新的知识治疗骨骼和其他器官疾病中骨质流失的治疗靶标。