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：
10595042
负责人：
Matthew L Warman
金额：
$ 40.57万
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/10595042
关键词：
Affect African American Aging Alleles American Animal Behavior Animals Apatites Behavioral Biological Biological Markers Biological Process Biology Blinded Blood Glucose Body mass index Bone Density Boston Brain Child Cognition Cultured Cells Data 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 Investments 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 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 bisphosphonate bone bone mass bone strength brain malformation cohort college conflict resolution 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

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。根据使用进行的研究骨钙素敲除（KO）小鼠的 Ocnm1 品系，骨钙素被认为是一种骨源性激素，调节葡萄糖代谢、脂肪储存、男性生育能力、肌肉质量、大脑发育和认知。这些骨钙素的新颖且令人兴奋的作用导致了对小鼠和人类的许多下游研究，这些研究产生了不一致甚至矛盾的结果。两个独立产生并检查的新菌株骨钙素 KO 小鼠（Bglap/2dko 和 Ocn-）没有异常的糖代谢、脂肪储存、雄性生育能力、或肌肉质量；未对 2 个新 KO 菌株的神经表型进行检查。不一致的发现原始 (Ocnm1) 和新 (Bglap/2dko 和 Ocn-) 骨钙素 KO 菌株之间的差异带来了挑战和机会。面临的挑战是确定哪些最初报道的激素表型是稳健的（即，真实的阳性），以及这些表型是否可能在新的 KO 菌株中被遗漏（即假阴性）。如果先前发布的数据正确，就会出现机会，因为这意味着之间的差异特定的 KO 等位基因、遗传背景（例如 129 与 C57）或环境（例如饮食、微生物组）饲养（或研究）哪些动物决定骨钙素缺乏是否以及如何影响新陈代谢、生育能力、衰老和认知。我们将确定原始 Ocnm1 KO 菌株中的哪些发现以及 Bglap/2dko KO 菌株中的特征是否稳健，以及是否存在任何一致的表型（例如行为、骨骼磷灰石晶体取向）跨应变。现在这两种菌株都可以从 The 获得，这些都是可能的杰克逊实验室（JAX）。 JAX 将扩大其最大安全动物园中的每种菌株，以最大程度地减少对环境的影响混杂因素。 JAX 将对每个品系的动物进行基因分型，并将其运送到研究代谢、生殖、肌肉、神经和骨骼表型；这些专家实验室将进行盲法表型分析动物品系（Ocnm1 或 Bglap/2dko）和基因型（WT 或 KO）。表型数据将发送至研究统计学家、PI 和数据审查小组进行审查。数据审查小组有 4 名骨骼生物学专家，全部是美国骨与矿物质研究学会前任主席。源自该作品的手稿将发布在 BioRxiv 上并提交给开放获取、同行评审的期刊。表现力强，使用在公共环境中饲养的公开小鼠进行盲法研究，并由专家实验室进行研究，并由骨骼生物学领域受人尊敬的领导人进行审查对于解决有关骨骼生物学的冲突至关重要骨钙素的内源性作用以及识别因素（例如 KO 等位基因、遗传背景、环境）这可能会改变小鼠品系之间和人群之间骨钙素缺乏的影响。