Skeletal and non-skeletal roles for osteocalcin

骨钙素的骨骼和非骨骼作用

基本信息

批准号：
10417887
负责人：
Matthew L Warman
金额：
$ 39.81万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10417887
关键词：
Affect African American Aging Alleles American Animal Behavior Animals Apatites Behavioral Biological Biological Process Biology Blinded Blood Glucose Body mass index Bone Density Boston Brain Child Cognition Conflict (Psychology)Crystallization Cultured Cells Data Data Reporting Deposition Development Diabetes Mellitus Diet Dietary intake Disease Drug Targeting Ear Endocrine Energy Metabolism Ensure Environment Environmental Exposure Evolution Failure Fatty acid glycerol esters Fertility Funding Agency Genetic Genetic Variation Genotype Glucose Glucose Clamp Glycosylated hemoglobin A Grant Health Hormonal Hormones Hospitals Human Human Resources Hydroxyapatites Hyperglycemia Impaired cognition Impairment Individual Induced Mutation Insulin Insulin Resistance Journals Knock-out Knockout Mice Laboratories Learning Letters Literature Manuscripts Measures Medicine Metabolic Metabolism Minerals Morphology Mouse Strains Mus Muscle Nature Neurologic Osteocalcin Patients Pediatric Hospitals Peer Review Pharmacologic Substance Phenotype Physiology Population Post-Translational Protein Processing Production Property Proteins Publishing Quarantine Rattus Recombinants Reporting Reproducibility Reproduction Reproductive Biology Research Resources Risk Role Science Ships Societies Sperm Count Procedure Testis The Jackson Laboratory Therapeutic Therapeutic Agents Translating United States National Institutes of Health Universities Validation Vitamin K Work age-related muscle loss base bisphosphonate bone bone mass bone strength brain malformation cohort college experimental study fascinate fighting follower of religion Jewish genome wide association study glucose metabolism glucose tolerance inhibitor insulin tolerance loss of function loss of function mutation male fertility medical schools metabolic abnormality assessment metabolic phenotype microbiome muscle form nanoindentation novel phenotypic data programs protein function reproductive reproductive hormone response skeletal targeted biomarker

项目摘要

Osteocalcin is among the most highly expressed proteins in bone. Based on studies performed using the Ocnm1 strain of osteocalcin knockout (KO) mice, osteocalcin was suggested to be a bone-derived hormone that regulates glucose metabolism, fat storage, male fertility, muscle mass, brain development, and cognition. These novel and exciting roles for osteocalcin led to many downstream studies in mice, and in humans, which yielded inconsistent and even contradictory results. Two independently generated and examined new strains of osteocalcin KO mice (Bglap/2dko and Ocn-) did not have abnormal glucose metabolism, fat storage, male fertility, or muscle mass; neurologic phenotypes were not examined in the 2 new KO strains. The inconsistent findings between the original (Ocnm1) and new (Bglap/2dko and Ocn-) osteocalcin KO strains creates a challenge and an opportunity. The challenge is to determine which originally reported hormonal phenotypes are robust (i.e., true positives), and whether these phenotypes may have been missed (i.e., false negatives) in the new KO strains. Opportunity arises if the previously published data are correct, since this would mean that differences between the specific KO allele, the genetic background (e.g., 129 vs C57), or the environment (e.g., diet, microbiome) in which animals were raised (or studied) are responsible for whether and how osteocalcin deficiency affects metabolism, fertility, ageing, and cognition. We will determine which findings in the original Ocnm1 KO strain and in the Bglap/2dko KO strain are robust, and whether there are any consistent phenotypes (e.g., behavioral, bone apatite crystal orientation) across strains. These are possible now that both strains are available from The Jackson Laboratory (JAX). JAX will expand each strain in its maxi-safe vivarium to minimize environmental confounders. JAX will genotype and ship animals from each strain to laboratories expert in studying metabolic, reproductive, muscle, neurologic, and skeletal phenotypes; these expert labs will perform phenotyping blinded to animal strain (Ocnm1 or Bglap/2dko) and genotype (WT or KO). Phenotype data will be sent to the study statistician, PI, and Data Review Panel for review. The Data Review Panel has 4 expert skeletal biologists, all past-Presidents of the American Society for Bone and Mineral Research. Manuscripts deriving from this work will be posted on BioRxiv and submitted to open-access, peer-reviewed, journals. Performing well-powered, blinded studies using publicly available mice raised in a common environment, studied by expert laboratories, and reviewed by respected leaders in the field of skeletal biology is essential for resolving conflicts regarding the endogenous role of osteocalcin and for identifying factors (e.g., KO allele, genetic background, environment) that may modify the effect of osteocalcin deficiency between mouse strains and between human populations.

骨钙素是骨骼中表达最高的蛋白质之一。基于使用骨钙蛋白敲除（KO）小鼠的OCNM1菌株，建议骨钙素是一种骨源性激素调节葡萄糖代谢，脂肪储存，男性生育能力，肌肉质量，脑发育和认知。这些骨钙素的新颖而令人兴奋不一致甚至矛盾的结果。两个独立生成并检查了新的菌株骨钙蛋白KO小鼠（BGLAP/2DKO和OCN-）没有异常的葡萄糖代谢，脂肪储存，男性生育力，或肌肉质量；在2种新的KO菌株中未检查神经系统型。不一致的发现在原始（OCNM1）和新的（BGLAP/2DKO和OCN-）之间，骨钙蛋白KO菌株造成了挑战和一个机会。挑战是确定哪些最初报道的激素表型是可靠的（即正确的阳性），以及在新的KO菌株中是否可能错过了这些表型（即假阴性）。如果先前发布的数据正确，就会出现机会，因为这意味着特定的KO等位基因，遗传背景（例如129 vs C57）或环境（例如饮食，微生物组）饲养哪些动物（或研究）是负责骨钙素缺乏症的影响以及如何影响代谢，生育能力，衰老和认知。我们将确定原始OCNM1 KO菌株中的哪些发现和在bglap/2dko ko菌株中，菌株是否稳健，是否有任何一致的表型（例如，行为，骨头磷灰石晶体取向）跨应变。现在可以从两种菌株中获得这些菌株杰克逊实验室（JAX）。 JAX将在其最大安全性中扩展每个菌株，以最大程度地减少环境混淆者。 JAX将基因型和动物从每种菌株到实验室专家研究代谢，生殖，肌肉，神经系统和骨骼表型；这些专家实验室将表现出盲目的表型到动物菌株（OCNM1或BGLAP/2DKO）和基因型（WT或KO）。表型数据将发送到研究统计学家，PI和数据审核面板进行审查。数据审查面板有4位专家骨骼生物学家美国骨骼和矿物研究学会的前任主席。这项工作衍生的手稿将发布在Biorxiv上，并提交给经同行评审的Open-Access。表现良好，使用专家实验室研究的共同环境中提出的公开小鼠的盲目研究，在骨骼生物学领域受到尊敬的领导者进行审查，对于解决有关的冲突至关重要骨钙素和识别因子的内源作用（例如KO等位基因，遗传背景，环境）这可能会改变小鼠菌株和人群之间骨钙素缺乏症的影响。