Muscle Fibrosis in Cachexia

项目总结 恶病质是一种肌肉萎缩综合征，影响一半的癌症患者和四分之一的 慢性病。科学上讲，恶病质的定义是肌肉萎缩，同时伴有全身炎症(例如，IL-1)。 6信令)。恶病质存在于导致进行性功能衰退和难治性末梢的谱系上- 舞台。顽固性恶病质对初级治疗、消炎治疗或锻炼没有反应， 这些措施在早期阶段有效。恶病质向难治期过渡的关键调节因素是 未知。持续性炎症导致组织细胞外基质(ECM)重塑和纤维化。在肌肉方面， ECM调节肌肉的生理和功能，这在疾病中可能会被破坏。而肌肉 纤维化与癌症患者死亡率的增加、细胞外基质与难治性恶病质的关系有关 是未知的。由于目前临床前恶病质模型的设计不能区分早期和难治性恶病质 阶段生物学，我们开发了一种新的小鼠模型，延长了寿命，扩大了探索的机会 早期和难治性恶病质现象。这个应用程序的科学目标是确定 在我们的新模型中，肌肉纤维化是难治性恶病质治疗反应的障碍。目标1 早期和难治性抗IL-6和抗纤维化治疗的单独和联合作用的研究 恶病质分期对肌肉力学、功能、消瘦和存活率的影响。我们假设双重待遇 使用消炎药和抗纤维化药物将恢复以前难治阶段的恶病质表型。 目的2直接检测恶病质相关的纤维化在运动反应中的作用。我们假设反- 纤维化治疗将提高耐力训练和抵抗训练在难治性疾病中的疗效 恶病质。这些研究将扩大我们对顽固性恶病质生物学的了解，拓宽我们的 了解细胞外基质在恶病质中的作用，并启动协同治疗的临床前评估。 这是一份申请K08职业发展奖的申请书，该奖项授予伊山·罗伊，医学博士，内科科学家 雪莉·瑞安能力实验室(SRALab)，物理医学系助理教授 在西北大学(NU)康复。这个应用程序的职业目标是Roy博士获得专业知识 在肌肉生理学、运动科学和细胞外基质生物学领域。再结合他之前在 在学习免疫学和癌症生物学之后，罗伊博士将把他的新培训应用到恶病质生物学领域。理查德 利伯博士是肌肉生理学和康复方面的主要导师和专家。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都做出了重要的 对罗伊博士职业发展的承诺和这份申请代表着建立一个 指导和培训计划，以实现罗伊博士独立的职业目标。

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.