Age-Induced Impairment of Nutrient Signaling Results in Bone Loss

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。

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.