Gut microbial factors that increase bone tissue strength

项目摘要/摘要 在美国，与年龄相关的脆性骨折每年造成的医疗成本超过250亿美元。风险 脆性骨折的主要原因是骨密度(骨量)和骨组织质量的降低。 目前骨质疏松症的治疗方法在增加骨量方面是有效的，但并没有直接针对 骨组织质量方面(骨基质的内容和组织)。最近有几项研究 发现了肠道微生物群的组成和骨骼强度之间的联系。之前的工作来自 赞助商的研究小组已经证明，对肠道微生物群组成的干扰可以损害 骨组织材料特性。一项更新的、意想不到的、令人兴奋的发现证明了这一点 肠道微生物群组成的改变增加了骨基质的强度。前期工作 生成了一份在骨组织增强的动物中数量增加的微生物分类群清单 相对于未更改的控件的强度。然而，特定的物种和功能能力 导致骨骼强度增加的细菌仍有待阐明。此外，先前的研究 操纵肠道微生物区系的成分主要是在年轻的雄性小鼠身上完成的。自.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 肠道微生物区系的相同变化可以影响老年动物的骨组织强度，无论性别。这 提案解决了以下问题：什么是分类和功能成分 微生物群负责增加小鼠的骨组织强度；是否有可能增加骨组织的强度 在成年后期通过改变肠道微生物群来改变骨基质？具体目标是：1)分离肠道 有助于幼鼠骨组织强度增加的微生物成分和2)决定 改善肠道微生物区系以提高老龄小鼠骨组织强度的效果。的首要目标是 这项提议是分离和鉴定肠道微生物区系中增强骨组织强度的成分。 以及生长和衰老小鼠的质量。这项提案的研究建立在 赞助商的小组，同时使候选人能够通过获得专业知识过渡到独立调查人员 在活体模型和微生物组元基因组分析中。候选人的长期目标是追求一种 致力于开发输送系统/生物材料，以调节微生物组的组成 应用如肌肉骨骼疾病和衰老。调节细胞生长的生物材料的发展 微生物区系需要在活体模型中对微生物区系进行分类和元基因组分析的知识。 因此，这项应用是为了资助肠道微生物组的活体实验和操作方面的培训 同时增加骨科研究的专业知识。训练活动还将包括接触团队科学， 授予写作，以及微生物组的教学课程作业。

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.