Gut microbial factors that increase bone tissue strength

增加骨组织强度的肠道微生物因素

• 批准号: 10537826
• 负责人: Erika Leah Cyphert
• 金额: $ 6.72万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537826
• 关键词: 16S ribosomal RNA sequencing; Activities of Daily Living; Address; Adult; Age; Age-Months; Aging; Animals; Antibiotics; Bacteria; Biocompatible Materials; Biological; Bone Density; Bone Matrix; Bone Tissue; Chronic; Elderly; Exhibits; Exposure to; Fracture; Funding; Genes; Goals; Grant; Health Care Costs; Healthcare Systems; Human; Impairment; Individual; Intervention; Knock-out; Knowledge; Lead; Life; Link; Measures; Metagenomics; Methods; Microbe; Modification; Morbidity - disease rate; Mus; Musculoskeletal Diseases; Orthopedics; Osteoporosis; Osteoporosis prevention; Outcome; Property; Public Health; Research; Research Personnel; Research Proposals; Research Training; Risk; Science; Shotguns; Source; System; Taxonomy; Therapeutic; Training; Training Activity; United States; Work; Writing; age related; aged; base; biomaterial development; bone; bone quality; bone strength; career; fragility fracture; gut bacteria; gut microbes; gut microbiome; gut microbiota; improved; in vivo; in vivo Model; male; metagenomic sequencing; microbial; microbiome; microbiota; mortality; osteoporosis with pathological fracture; prevent; sex

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.

项目概要/摘要 在美国，与年龄相关的脆性骨折每年造成的医疗费用超过 250 亿美元。 脆性骨折的发生是由于骨矿物质密度（骨量）和骨组织质量下降所致。 目前骨质疏松症的治疗方法可以有效增加骨量，但不能直接解决骨质疏松症的问题。 最近有几项研究表明骨组织质量（骨基质的内容和组织）。 先前的研究发现肠道微生物组的组成与骨骼强度之间存在联系。 申办者小组已经证明，对肠道微生物组成分的干扰可能会损害 最近的一项意外且令人兴奋的发现证明了这种特定的特性。 肠道微生物组组成的改变增加了骨基质的强度。 生成了一份微生物类群列表，这些微生物类群在骨组织增强的动物中丰度增加 然而，特定物种和功能能力的相对强度未改变。 此外，之前的研究还需要阐明有助于增加骨强度的细菌。 从那时起，对肠道微生物群成分的操纵主要是在年轻的雄性小鼠中完成的。 预防脆性骨折的干预措施最有可能适用于老年人，因此确定是否可以采取预防脆性骨折的干预措施至关重要 肠道微生物群的相同变化会影响老年动物的骨组织强度。 该提案解决了以下问题：生物的分类和功能组成部分是什么？ 微生物群负责增加小鼠骨组织的强度；是否有可能增加骨组织的强度； 通过改变成年晚期肠道微生物群来改变骨基质？具体目标是 1) 隔离肠道 有助于增加幼鼠骨组织强度的微生物成分，2) 确定 改变肠道微生物群以增加老年小鼠骨组织强度的效果。 该提案旨在分离和表征增强骨组织强度的肠道微生物群成分 该提案的研究建立在先前研究结果的基础上。 赞助商小组，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 职业发展输送系统/生物材料，调节微生物组的成分 开发调节肌肉骨骼疾病和衰老的生物材料。 微生物群需要了解体内模型中微生物群的分类学和宏基因组分析。 因此，该申请旨在资助肠道微生物组的体内实验和操作培训 在增加骨科研究专业知识的同时，培训活动还将包括接触团队科学， 资助写作和微生物组教学课程。