Gut microbial factors that increase bone tissue strength

项目总结/摘要 在美国，与骨质疏松相关的脆性骨折每年造成超过250亿美元的医疗费用。风险 脆性骨折的发生是由于骨矿物质密度（骨量）和骨组织质量降低。 目前骨质疏松症的治疗方法在增加骨量方面是有效的，但不能直接解决 骨组织质量方面（骨基质的含量和组织）。最近的几项研究 发现了肠道微生物组的组成与骨骼强度之间的联系。以前的工作从 发起人的小组已经证明，对肠道微生物组成分的干扰可以损害 骨组织材料特性。最近，一个意想不到的令人兴奋的发现表明， 肠道微生物组组成的改变增加了骨基质的强度。先前工作 生成了一个微生物分类群的列表，这些微生物分类群在骨组织增强的动物中丰度增加 相对于未改变的对照。然而，具体的物种和功能能力的 有助于增加骨强度的细菌仍有待阐明。此外，先前的研究 操纵肠道微生物群的组分主要在年轻的雄性小鼠中完成。以来 预防脆性骨折的干预措施最有可能适用于老年人，关键是要确定 在两种性别的老年动物中，肠道微生物群的相同改变可以影响骨组织强度。这 该提案涉及以下问题： 负责增加小鼠骨组织强度的微生物群;以及是否有可能增加 通过改变成年后期的肠道微生物群来改变骨基质？具体目的是：1）分离肠 有助于增加幼鼠骨组织强度的微生物成分和2）确定 改变肠道微生物群以增加老年小鼠骨组织强度的作用。的首要目标 该建议是分离和表征增强骨组织强度的肠道微生物群的成分， 和衰老小鼠的质量。这项提案的研究建立在以前的调查结果的基础上， 同时使候选人能够通过获得专业知识过渡到独立调查员 在体内模型和微生物组宏基因组分析中。候选人的长期目标是追求一个 职业发展输送系统/生物材料，调节微生物组的成分， 应用，如肌肉骨骼疾病和衰老。开发生物材料， 微生物群需要体内模型中微生物群的分类学和宏基因组学分析的知识。 因此，这项申请是为了资助肠道微生物组的体内实验和操纵方面的培训。 同时增加骨科专业研究。培训活动还将包括接触团队科学， 资助写作和微生物组的教学课程。

PROJECT SUMMARY/ABSTRACT Age-related fragility fractures impose healthcare costs exceeding $25 billion annually in the United States. Risk of fragility fracture is due to both decreased bone mineral density (bone quantity) and bone tissue quality. Current therapeutics for osteoporosis are effective at increasing bone quantity but do not directly address aspects of bone tissue quality (the contents and organization of the bone matrix). Several studies have recently discovered a link between the composition of the gut microbiome and bone strength. Previous work from the sponsor’s group has demonstrated that perturbations to the constituents of the gut microbiome can impair bone tissue material properties. A more recent, unexpected, and exciting finding demonstrated that specific alterations of the composition of the gut microbiome increased the strength of the bone matrix. Prior work generated a list of microbial taxa that had an increased abundance in animals with enhanced bone tissue strength relative to unaltered controls. Nevertheless, the specific species and functional capacity of the bacteria contributing to the increased bone strength remain to be elucidated. Additionally, prior studies manipulating the components of the gut microbiota were predominantly completed in young, male mice. Since interventions to prevent fragility fractures are most likely applied to older adults, it is critical to determine if the same alterations in the gut microbiota can influence bone tissue strength in aged animals of both sexes. This proposal addresses the following questions: what are the taxonomic and functional constituents of the microbiota responsible for increasing bone tissue strength in mice; and is it possible to increase the strength of the bone matrix by altering the gut microbiota in late adulthood? The specific aims are to 1) isolate gut microbial constituents contributing to increased bone tissue strength in young mice and 2) determine the effects of modifying the gut microbiota to increase bone tissue strength in aged mice. The overarching goal of the proposal is to isolate and characterize constituents of the gut microbiota that enhance bone tissue strength and quality in growing and aged mice. Research from this proposal builds upon prior findings from the sponsor’s group while enabling the candidate to transition to an independent investigator by gaining expertise in in vivo models and microbiome metagenomic analysis. The long-term goal of the candidate is to pursue a career developing delivery systems/biomaterials that regulate the constituents of the microbiome for applications such as musculoskeletal disorders and aging. Development of biomaterials that regulate the microbiota requires knowledge of taxonomic and metagenomic analysis of microbiota in in vivo models. Therefore, this application is to fund training in in vivo experimentation and manipulation of the gut microbiome while increasing expertise orthopaedic research. Training activities will also include exposure to team science, grant writing, and didactic coursework in the microbiome.