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

 描述（由申请人提供）：手术是老年人中非常常见和重要的治疗方法，在这些脆弱的个体中，手术后经常引起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K 08项目是实现这一目标的关键第一步。这项研究将在 James J. Peters VAMC由Fred Ko博士，医学博士，一位接受过临床老年病学和基础及临床转化研究培训的初级研究员。这项研究独特地关注衰老和肌肉生物学，手术压力和身体活动的交叉，以及动物模型的强度，以机械地测试关于术后身体衰退的生物学和治疗的假设。在目的1中，将利用多种分子和细胞生物学技术和动物行为测试来确定剖腹手术对年轻和老年C57 BL/6小鼠的术后期的腓肠肌生物学（IGF-1/IRS/PI 3 K/Akt和TNF α信号传导、肌肉蛋白合成）和行为表型（握力、自发活动、平衡）的影响。在目标2中，将使用相同的实验室技术确定术前踏车运动训练、术后功能阻断TNF α抗体给药及其联合治疗对腓肠肌生物学和行为表型的影响。据推测，在老年小鼠中，手术通过改变IGF-1/IRS/PI 3 K/Akt和TNF α活性诱导术后肌无力和身体衰退，并且通过运动和TNF α阻断的围手术期干预减轻了这些不利的分子、肌肉和身体变化。该项目的研究结果可能会确定候选分子，以及减轻术后肌肉无力和身体衰退的治疗方法。因此，源于K 08的实验室到床边研究可能会促进围手术期策略的制定，从而改善脆弱老年患者的手术结局。 已提出一项综合职业发展和辅导计划，以确保该项目的圆满完成和高博士向独立过渡。培训目标集中在高博士在肌肉生物学、肌肉研究优化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，以及他在奖励期内成功获得独立研究资助。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、教学法、研讨会、国家会议以及与资深科学家小组经常和定期举行的会议。Ko博士的科学和职业发展将由Christopher Cardozo博士（主要导师;肌肉生物学），Charles Mobbs博士（共同导师;衰老生物学），Gregory Elder博士（贡献者;行为测试），Shalender Bhasin博士（贡献者;运动干预），Janice Gabrilove博士（贡献者;生物学）和Joan Penrod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).