Post-operative Muscle and Physical Decline in Aged Organism: Mechanisms and Interventions

 描述(由申请人提供)：手术是老年人非常常见和重要的治疗方法，在这些脆弱的人手术后经常会导致严重的肌肉无力和身体衰退。因此，围手术期的优化。 护理是改善老年患者手术结果和生活质量的关键。拟议的K08项目是实现这一目标的关键的第一步。这项研究将在 詹姆斯·J·彼得斯VAMC，由弗雷德·科博士撰写，他是一名初级研究员，接受过临床老年病学以及基础和临床翻译研究方面的培训。这项研究独特地聚焦于衰老和肌肉生物学、手术应激和体力活动的交叉，以及动物模型的强度，以机械地测试关于手术后身体衰退的生物学和治疗的假说。目的1利用多种分子和细胞生物学技术及动物行为学测试，研究剖腹手术对青年和老年C57BL/6小鼠术后腓肠肌生物学(IGF1/IRS/PI3K/Akt和肿瘤坏死因子信号转导、肌肉蛋白质合成)和行为表型(握力、活动、平衡)的影响。目的2采用相同的实验室技术，研究术前跑台运动训练、术后功能阻断肿瘤坏死因子抗体应用及其联合治疗对腓肠肌生物学和行为表型的影响。假设手术通过改变IGF1/IRS/PI3K/Akt和肿瘤坏死因子活性导致老年小鼠术后肌肉无力和身体衰退，而围手术期运动干预和肿瘤坏死因子阻断减轻了这些不利的分子、肌肉和生理变化。这个项目的发现可能会确定控制术后肌肉无力和身体衰退的候选分子，以及减轻这些疾病的治疗方法。因此，基于K08的床到床研究可能会促进围手术期策略的发展，从而改善脆弱的老年患者的手术结果。已经提出了一个综合的职业发展和指导计划，以确保这个项目的成功完成和高博士向独立的过渡。培训目标集中于Ko博士在肌肉生物学、优化肌肉研究的分子和细胞生物学技术、小鼠行为测试方面的专业知识的发展，以及他在获奖期内成功竞争独立研究拨款。这些目标将通过严格的培训活动来实现，其中包括正式的课程工作、教学、研讨会、全国会议以及与资深科学家团队的频繁和预定的会议。Ko博士的科学和职业发展将由克里斯托弗·卡多佐医学博士(主要导师；肌肉生物学)、查尔斯·莫布斯博士(共同导师；衰老生物学)、格雷戈里·埃尔德医学博士(贡献者；行为测试)、谢伦德·巴辛医学博士(贡献者；运动干预)、贾尼斯·加布里洛夫医学博士(贡献者；生物学)和琼·彭罗德博士(贡献者；统计方法)指导。

 DESCRIPTION (provided by applicant): Surgery, a very common and important therapeutic treatment in older adults, frequently induces profound muscle weakness and physical decline in the post-operative period in these vulnerable individuals. Thus, the optimization of peri-operative care is the key to improving surgical outcomes and quality of life in older patients. The proposed K08 project is a critical first step towards meeting this goal. This study will be conducted at the James J. Peters VAMC by Dr. Fred Ko, MD, a junior investigator with training in clinical geriatrics and basic and clinical translational research. This study uniquely focuses on the intersection of aging and muscle biology, surgical stress, and physical activity, and on the strength of animal models, to mechanistically test hypotheses regarding the biology and treatments of post-operative physical decline. In Aim 1, the effects of laparotomy on gastrocnemius muscle biology (IGF-1/IRS/PI3K/Akt and TNF signaling, muscle protein synthesis) and behavioral phenotype (grip strength, locomotor activity, balance) in the post- operative period of young and aged C57BL/6 mice will be determined utilizing a variety of molecular and cell biology techniques and animal behavioral testing. In Aim 2, the effects of pre-operative treadmill exercise training, post-operative functional blocking TNF antibody administration, and their combination therapy on gastrocnemius muscle biology and behavioral phenotype will be determined using the same laboratory techniques. It is hypothesized that in aged mice surgery induces post-operative muscle weakness and physical decline by altering IGF-1/IRS/PI3K/Akt and TNF activity, and that peri-operative interventions with exercise and TNF blockade attenuate these adverse molecular, muscular, and physical changes. The findings from this project will likely identify candidate molecules that govern, and treatments tha attenuate, post-operative muscle weakness and physical decline. Thus, bench-to-bedside research that stems from this K08 will likely facilitate development of peri-operative strategies that improve surgical outcomes in vulnerable older patients. An integrated career development and mentoring plan has been proposed to ensure this project's successful completion and Dr. Ko's transition to independence. The training goals are centered on Dr. Ko's development of expertise in muscle biology, molecular and cell biology techniques optimized for muscle research, mouse behavioral testing, and his successful competition of an independent research grant within the award period. These goals will be met with rigorous training activities that include formal course work, didactics, seminars, national conferences, and frequent and scheduled meetings with a team of senior scientists. Dr. Ko's scientific and career development will be guided by Christopher Cardozo, MD (primary mentor; muscle biology), Charles Mobbs, PhD (co-mentor; aging biology), Gregory Elder, MD (contributor; behavioral testing), Shalender Bhasin, MD (contributor; exercise intervention), Janice Gabrilove, MD (contributor; biologics), and Joan Penrod, PhD (contributor; statistical methods).