Muscle Fibrosis in Cachexia

恶病质中的肌肉纤维化

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要恶氧化疾病是一种浪费肌肉综合征，影响了所有癌症患者的一半，所有患者中有四分之一慢性疾病。从科学上讲，卡氏症是由平行于全身感染的肌肉损失所定义的（例如IL- 6信号）。恶病质存在于导致渐进式功能下降和难治性端的频谱中阶段。难治性的缓存对原发治疗，抗炎疗法或运动不反应在较早的阶段有效。过渡到卡希克西难治阶段的关键调节因子是未知。持续注射会导致组织外基质（ECM）重塑和纤维化。在肌肉中 ECM调节肌肉生理和功能，可能会在疾病中破坏。而肌肉纤维化与癌症患者的死亡率增加有关，ECM与难治性恶病质之间的关系是未知的。由于当前的恶病质临床前模型并非旨在区分早期和难治性阶段生物学，我们开发了一种具有延长寿命的新鼠标模型，扩大了证明的机会早期和耐火阶段的恶病质现象。本应用的科学目标是确定是否肌肉纤维化是我们新型模型中难治性恶病质治疗反应能力的障碍。目标1 研究抗IL-6和抗纤维化治疗的个体和综合作用在早期和难治性肌肉力学，功能，浪费和生存的卡希克西亚阶段。我们假设双重治疗抗炎和抗纤维化将在先前难治性阶段恢复恶病质表型。 AIM 2直接研究了与运动相关的纤维化相关纤维化的作用。我们假设反 - 纤维化疗法将提高难治期间耐力和耐药性运动的效率卡希克西亚。这些研究将扩大我们对难治性恶病质生物学的了解，扩大了我们的知识了解ECM在恶病质中的作用，并开始对协同疗法的临床前评估。这是Ishan Roy，医学博士，博士学位的K08职业发展奖的申请雪莉·瑞安（Shirley Ryan）的能力拉布（Sralab）和物理医学系的助理教授和西北大学（NU）康复。该应用的职业目标是罗伊博士获得专业知识在肌肉生理，运动科学和ECM生物学领域。结合他先前的背景免疫学和癌症生物学，罗伊博士然后将他的新培训应用于卡希克西生物学领域。理查德利伯（Lieber），博士是肌肉生理和康复的主要精神，也是专家。 G.R.斯科特·布丁（Scott Budinger）， MD是炎症和组织纤维化方面的专家。 Sralab和Nu都表现出色对罗伊博士的职业发展的承诺，这一申请代表了建立一个的下一步实现罗伊博士的职业独立目标的识别和培训计划。