Muscle Fibrosis in Cachexia

恶病质中的肌肉纤维化

• 批准号: 10506281
• 负责人: Ishan Roy
• 金额: $ 17.04万
• 依托单位: REHABILITATION INSTITUTE OF CHICAGO D/B/A SHIRLEY RYAN ABILITYLAB
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10506281
• 关键词: Affect; Animal Model; Animals; Anti-Cytokine Therapy; Anti-Inflammatory Agents; Antiinflammatory Effect; Articular Range of Motion; Biological Assay; Biological Models; Biology; Blocking Antibodies; Cachexia; Cancer Biology; Cancer Patient; Chronic Disease; Clinical; Clinical Trials; Collagen; Development; Disease; Disease model; Disuse Atrophy; Doctor of Philosophy; Elasticity; Exercise; Extracellular Matrix; Failure; Fiber; Fibroblasts; Fibrosis; Frequencies; Future; Goals; Hand Strength; Histology; Human; Hydroxyproline; Hypertrophy; IL-6 inhibitor; Immune system; Immunology; Individual; Inflammation; Inflammatory; Interleukin-1; Interleukin-6; Intervention; Intramuscular; K-Series Research Career Programs; Knowledge; Link; Longevity; Losartan; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Mechanics; Mentors; Mentorship; Modeling; Morbidity - disease rate; Mus; Muscle; Muscle Development; Muscle function; Muscle rehabilitation; Muscular Atrophy; Organ failure; Patients; Phase; Phenotype; Physical Function; Physical Medicine; Physical Rehabilitation; Physicians; Physiology; Play; Pre-Clinical Model; Protein-Lysine 6-Oxidase; Refractory; Resistance; Role; Rotarod Performance Test; Running; Scheme; Science; Scientist; Signal Transduction; Skeletal Muscle; Syndrome; TNF gene; Testing; Tissues; Training; Transforming Growth Factor beta; Universities; Wasting Syndrome; Weight; Weight-Bearing state; Work; age related; antifibrotic treatment; autocrine; career; career development; chronic infection; cohort; crosslink; cytokine; endurance exercise; exercise intervention; exercise regimen; functional decline; functional improvement; implantation; improved; in vivo; inhibitor; mortality; mouse model; multimodality; muscle physiology; novel; preclinical evaluation; prevent; professor; rehabilitation strategy; resistance exercise; response; sarcopenia; skills; success; systemic inflammatory response; treadmill; treatment response; wasting

Project summary Cachexia is a muscle-wasting syndrome that affects half of all cancer patients and a quarter of all patients with chronic diseases. Scientifically, cachexia is defined by muscle loss in parallel to systemic inflammation (e.g. IL- 6 signaling). Cachexia exists on a spectrum that leads to progressive functional decline and a refractory end- stage. Refractory cachexia is not responsive to primary treatment, anti-inflammatory therapies, or exercise, which are effective in earlier phases. The key regulators of the transition to the refractory phase of cachexia are unknown. Sustained inflammation leads to tissue extracellular matrix (ECM) remodeling and fibrosis. In muscle, the ECM regulates muscle physiology and function, which can become disrupted in disease. While muscle fibrosis is linked to increased mortality in cancer patients, the relationship between ECM and refractory cachexia is unknown. Since current preclinical models of cachexia are not designed to distinguish early and refractory phase biology, we developed a new mouse model with an extended lifespan, expanding the opportunity to probe early and refractory phase cachexia phenomena. The scientific goal of this application is to determine whether muscle fibrosis is a barrier to responsiveness to therapy in refractory cachexia in our novel model. Aim 1 investigates the individual and combine effects of anti-IL-6 and anti-fibrosis treatments at early and refractory stages of cachexia on muscle mechanics, function, wasting, and survival. We hypothesize that dual treatment with anti-inflammatories and anti-fibrotic will rehabilitate the cachexia phenotype at previously refractory stages. Aim 2 directly examines the role of cachexia related fibrosis in response to exercise. We hypothesize that anti- fibrotic therapies will improve the efficacy of both endurance and resistance exercises during the refractory cachexia. These studies will expand our knowledge of the biology of refractory cachexia, broaden our understanding of the role of ECM in cachexia, and initiate preclinical evaluation of synergistic therapies. This is an application for a K08 Career Development Award for Ishan Roy, MD, PhD, Physician Scientist at Shirley Ryan AbilityLab (SRAlab) and Assistant Professor at the Department of Physical Medicine and Rehabilitation at Northwestern University (NU). The career goal of this application is for Dr. Roy to gain expertise in the fields of muscle physiology, exercise science, and ECM biology. Combined with his prior background in immunology and cancer biology, Dr. Roy will then apply his new training to the field of cachexia biology. Richard Lieber, PhD is the primary mentor and an expert in muscle physiology and rehabilitation. G.R. Scott Budinger, MD is co-mentor and an expert in inflammation and tissue fibrosis. Both SRAlab and NU have made a significant commitment to Dr. Roy’s career development and this application represents the next step in establishing a mentorship and training plan to achieve Dr. Roy’s career goal of independence.

项目摘要 恶病质是一种肌肉消耗综合征，影响一半的癌症患者和四分之一的癌症患者。 慢性病科学上，恶病质定义为与全身性炎症平行的肌肉损失（例如IL-10）。 6信令）。恶病质存在于导致进行性功能下降和难治性终点的一系列疾病中- 阶段难治性恶病质对主要治疗、抗炎治疗或运动无反应， 这在早期阶段是有效的。恶病质向难治期转变的关键调节因子是 未知持续的炎症导致组织细胞外基质（ECM）重塑和纤维化。在肌肉中， ECM调节肌肉生理和功能，其在疾病中可能被破坏。而肌肉 纤维化与癌症患者死亡率增加有关，ECM与难治性恶病质之间的关系 不明由于目前恶病质的临床前模型并不能区分早期和难治性 相生物学，我们开发了一种新的小鼠模型，具有延长的寿命，扩大了探测的机会。 早期和难治性恶病质现象。这项申请的科学目标是确定 在我们的新模型中，肌肉纤维化是难治性恶病质治疗反应性的障碍。要求1 研究抗IL-6和抗纤维化治疗在早期和难治性的个体和联合收割机的作用， 恶病质阶段对肌肉力学、功能、消耗和存活的影响。我们假设双重治疗 使用抗炎药和抗纤维化药物将恢复先前难治阶段的恶病质表型。 目的2直接研究恶病质相关纤维化在运动中的作用。我们假设反- 纤维化治疗将提高在难治性心脏病期间耐力和阻力锻炼的功效， 恶病质这些研究将扩大我们对难治性恶病质生物学的认识，拓宽我们的研究领域。 理解ECM在恶病质中的作用，并启动协同疗法的临床前评价。 这是一个K 08职业发展奖的应用程序，医学博士，博士，医生科学家在 雪莉瑞安能力实验室（SRAlab）和物理医学系助理教授， 西北大学（NU）康复中心。此应用程序的职业目标是为罗伊博士获得专业知识 在肌肉生理学、运动科学和ECM生物学领域。结合他之前的背景 在学习了免疫学和癌症生物学之后，罗伊博士将把他的新训练应用于恶病质生物学领域。理查德 Lieber博士是主要的导师和肌肉生理学和康复方面的专家。G.R.斯科特·布丁格， MD是炎症和组织纤维化方面的共同导师和专家。SRAlab和NU都取得了重大进展， 致力于罗伊博士的职业发展，这一申请代表了建立一个 指导和培训计划，以实现罗伊博士的独立的职业目标。