Age-Induced Impairment of Nutrient Signaling Results in Bone Loss

描述(由申请人提供)：65岁以上的成年人中，每六人中就有一人每天摄入不到1,000卡路里的热量，在老年住院人口中，营养不良的患病率增加到23%至60%之间。正是这一人群面临着最大的骨折风险。我们假设，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。本计划项目申请的重点是确定营养素在年龄相关性骨丢失中的作用。该提案包括三个项目和三个核心设施。这三个研究项目将确定参与骨髓基质细胞(BMSC)分化和增殖的营养调控的分子机制，并将确定这些机制如何随着年龄的变化而改变。三个核心设施将为整个项目增加价值，为项目提供必要的支持，同时促进佐治亚医学院的衰老和骨骼研究。该提案的总体具体目标是：(1)确定衰老如何改变骨源性前体细胞对氨基酸的反应；(2)确定衰老如何改变骨和肌肉来源的干细胞对营养相关激素(如IGF-1和瘦素)的反应；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介导的骨髓间充质干细胞分化的转录调控。这一应用的主要优势包括：(1)具有不同分子生物学、生理学、内分泌学和骨生物学背景的研究人员的多学科团队，他们将带来新的视角来解决共同的问题；(2)强烈的临床-翻译重点，医学临床医生科学家和博士研究科学家都发挥着关键作用；(3)具有不同背景和培训的研究人员的混合体，他们共同工作了5年；(4)来自临床和研究部门以及MCG管理部门的杰出机构支持；以及(5)在高度集成的项目组件之间协调使用常见的衰老小鼠模型(C57BL/6)。不同项目之间的紧密结合使这项提议真正具有协同性和独特性。最终，我们期待该计划项目确定新的治疗策略，并针对与年龄相关的肌肉骨骼功能下降制定具体的对策。

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.