Age-Induced Impairment of Nutrient Signaling Results in Bone Loss

年龄引起的营养信号损伤导致骨质流失

• 批准号: 8079339
• 负责人: CARLOS M. ISALES
• 金额: $ 125.62万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8079339
• 关键词: Age; Induced; Impairment; Nutrient; Signaling

DESCRIPTION (provided by applicant): One out of every six adults over the age of sixty-five consumes less than 1,000 calories/day, and in the case of older, institutionalized populations the prevalence of malnutrition increases to between twenty-three to sixty percent. It Is precisely this population that is at greatest risk for bone fractures. We hypothesize that a decline in musculoskeletal function with age is due in large part to a decline in nutrient-activated anabolic signals. This Program Project application is focused on defining the role of nutrients in age-dependent bone loss. The proposal consists of three Projects and three Core facilities. The three research projects will define the molecular mechanisms involved in nutrient modulation of bone marrow stromal cell (BMSC) differentiation and proliferation, and will determine how these mechanisms are altered with aging. The three Core facilities will add value to the program as a whole by providing essential support to the Projects while at the same time promoting aging and bone research at the Medical College of Georgia. The overall specific aims of the proposal are: (1) To determine how aging alters the response of bone-derived progenitor cells to amino acids; (2) To determine how aging alters the response of bone-and muscle-derived stem cells to nutrition-related hormones (e.g., IGF-1 and leptin); and (3) To determine how aging and nutrient-related stimuli alter the transcriptional regulation of BMSC differentiation mediated by stromal derived factor-1. Major strengths of this application include: (1) a multidisciplinary team of investigators with diverse backgrounds in molecular biology, physiology, endocrinology, and bone biology, who will bring new perspectives to solve a common problem; (2) a strong clinical-translational focus, with both M.D. clinician scientists and Ph.D. research scientists playing key roles; (3) a mixture of investigators of diverse background and training who have been working together for five years; (4) outstanding institutional support from both clinical and research departments, as well as from the MCG administration; and (5) the coordinated use of a common model of aging mice (C57BL/6) across highly integrated project components. This tight integration among the different projects makes this proposal truly synergistic and unique. Ultimately, we expect the Program Project to identify new therapeutic strategies and develop specific countermeasures for age-associated declines in musculoskeletal function. PUBLIC HEALTH RELEVANCE: The studies described here will aid in the development of new strategies to treat and prevent age related bone loss. REVIEW OF INDIVUDUAL COMPONENTS CORE A: ADMINISTRATIVE AND BIOSTATISTICS CORE; Dr. Carlos Isales, Core Leader (CL). DESCRIPTION (provided by applicant): Administrative and biostatistical activities of the Program Project will take place in the Administrative Core. Drs. Isales and Hamrick will be responsible for the scientific oversight of the PPG, the direction of research emphasis and the fiscal administration. Dr. Isales will chair the Executive and Scientific Committee meetings and be responsible for preparing all progress reports for these two committees and for the NIA. Dr. Isales will consult with appropriate committee members and Project and Core Leaders in order to effectively resolve all personnel and fiscal issues that may arise. Dr. Isales will be the liaison to the NIA and will ensure that annual non-competing renewal reports and quarterly reports on participant accrual are reported promptly and accurately to the NIA. He will also oversee compliance with regard to MCG's Institutional Review Board's policies, including the requirement that all Project and Core investigators and staff maintain certification in MCG's Research Ethics Training Program. The main purpose of the Biostatistics component is to bring together the information from different sources into an integrated database, and to coordinate the statistical analyses with the focus being on the main goals of the PPG.The Biostatistics faculty will help the investigators of the projects to choose appropriate experimental designs and analytical techniques tailored to address specific hypotheses, especially, focusing on justification of the data analysis method to be used for each type of data generated. The Biostatistics component will serve as the focus for data compilation, quality control, data analysis and interpretation support for the PPG, including: 1. Design and apply analytical methods to be used in the quantitative studies associated with various projects in the PPG; 2. Provide ongoing statistical consultation to research projects, focusing on issues such as experimental design, sample size, aptness and validity of models to be used, power considerations, interpretation of results and preparation of manuscripts for presentations and publications; and 3. Maintain a dataflow system that insures accuracy, security, validation and archiving of all data collected for different projects of the PPG. PUBLIC HEALTH RELEVANCE: Core A will ensure that the Projects receive adequate support both for administrative issues and biostatistical analysis.

描述（由申请人提供）：六十五岁以上的成年人中，每六个人中就有一个人每天消耗不到1,000卡路里，在老年人中，机构化人口的营养不良患病率增加到百分之二十三到六十之间。正是这一人群骨折的风险最大。我们推测，随着年龄的增长，肌肉骨骼功能的下降在很大程度上是由于营养激活的合成代谢信号的下降。该计划项目应用程序的重点是定义营养素在年龄依赖性骨质流失中的作用。该项目包括三个项目和三个核心设施。这三个研究项目将确定骨髓基质细胞（BMSC）分化和增殖的营养调节所涉及的分子机制，并将确定这些机制如何随着衰老而改变。这三个核心设施将通过为项目提供必要的支持，同时促进格鲁吉亚医学院的老龄化和骨骼研究，为整个项目增加价值。该提案的总体具体目标是：（1）确定衰老如何改变骨源性祖细胞对氨基酸的反应;（2）确定衰老如何改变骨和肌肉源性干细胞对营养相关激素的反应（例如，IGF-1和瘦素）;以及（3）确定衰老和营养相关刺激如何改变基质衍生因子-1介导的BMSC分化的转录调节。该应用程序的主要优势包括：（1）具有分子生物学，生理学，内分泌学和骨生物学不同背景的多学科研究人员团队，他们将带来新的观点来解决常见问题;（2）强大的临床翻译重点，具有医学博士学位。临床科学家和博士研究科学家发挥关键作用;（3）不同背景和培训的研究人员的混合物，他们已经合作了五年;（4）来自临床和研究部门以及MCG管理部门的出色机构支持;（5）在高度集成的项目组件中协调使用常见的衰老小鼠模型（C57 BL/6）。不同项目之间的这种紧密结合使该提案真正具有协同性和独特性。最终，我们希望该计划项目能够确定新的治疗策略，并制定与年龄相关的肌肉骨骼功能下降的具体对策。 公共卫生相关性：这里描述的研究将有助于制定新的策略来治疗和预防年龄相关的骨质流失。 审查各个组成部分 核心A：管理和生物统计学核心;卡洛斯伊萨莱斯博士，核心负责人（CL）。 描述（由申请人提供）：计划项目的行政和生物统计活动将在行政核心中进行。Isales和Hamrick博士将负责PPG的科学监督、研究重点方向和财政管理。Isales博士将主持执行和科学委员会会议，并负责为这两个委员会和NIA编写所有进度报告。Isales博士将与适当的委员会成员和项目及核心领导人进行磋商，以有效解决可能出现的所有人事和财务问题。Isales博士将担任NIA的联络人，并将确保及时准确地向NIA报告年度非竞争性更新报告和参与者累积季度报告。他还将监督MCG机构审查委员会政策的合规性，包括要求所有项目和核心研究人员和工作人员保持MCG研究伦理培训计划的认证。生物统计学部分的主要目的是将来自不同来源的信息汇集到一个综合数据库中，并协调统计分析，重点是PPG的主要目标。生物统计学教师将帮助项目的研究人员选择合适的实验设计和分析技术，以解决特定的假设，特别是，侧重于对生成的每种数据类型使用的数据分析方法的合理性说明。生物统计部分将作为PPG的数据汇编、质量控制、数据分析和解释支持的重点，包括：1.设计和应用分析方法，用于与PPG中各种项目相关的定量研究; 2.为研究项目提供持续的统计咨询，重点关注实验设计、样本量、所用模型的适用性和有效性、功效考虑、结果解释以及报告和出版物手稿的准备等问题;维护一个数据库系统，确保PPG不同项目收集的所有数据的准确性、安全性、验证和存档。 公共卫生相关性：核心A将确保项目在行政问题和生物统计分析方面得到充分的支持。