权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

TWEAK/Fn14/UPR Signaling in Skeletal Muscle Wasting

骨骼肌萎缩中的 TWEAK/Fn14/UPR 信号转导

基本信息

批准号：
10660397
负责人：
ASHOK KUMAR
金额：
$ 55.16万
依托单位：
UNIVERSITY OF HOUSTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660397
关键词：
ATF6 gene Ablation Acceleration Adult Advanced Malignant Neoplasm Aging Antibodies ApcMin/+ mice Apoptosis Promoter Atrophic Attenuated Binding Cachexia Cancer Model Cancer Patient Cell Surface Receptors Chronic Chronic Disease Complication Denervation Development Disease Elderly Endoplasmic Reticulum Eukaryotic Initiation Factors Exercise Gene Expression Genetic Homeostasis In Vitro Individual Induction of Apoptosis Inflammation Inflammatory Inositol KRASG12D Knockout Mice Link Malignant Neoplasms Mediating Mediator Membrane Metabolic Metabolic dysfunction Mitochondria Modeling Molecular Mus Muscle Muscle Fibers Muscle function Muscular Atrophy Neuromuscular Junction Nutrient Organelles Oxidative Stress PRKR gene Pathway interactions Patients Phosphotransferases Population Prevention Prevention approach Prokaryotic Initiation Factor-2 Protein Biosynthesis Protein Secretion Proteins RNA Splicing Regulation Reporting Repression Role Signal Pathway Signal Transduction Skeletal Muscle Skeletal Muscle Neoplasm Stress Syndrome System TNF gene Therapeutic XBP1 gene activating transcription factor 1 aged arm cancer cachexia cell injury cytokine endoplasmic reticulum stress experimental study frailty improved in vivo knock-down member mouse model muscle form new therapeutic target novel novel therapeutic intervention novel therapeutics overexpression pancreatic cancer model pre-clinical prevent protein degradation protein folding receptor response sarcopenia sensor skeletal muscle differentiation skeletal muscle growth skeletal muscle wasting tissue degeneration tumor

项目摘要

ABSTRACT Skeletal muscle wasting/cachexia is a devastating complication of a number of chronic disease states, such as cancer and in the elderly population. Muscle wasting involves an imbalance in the rates of protein synthesis and degradation, functional denervation, metabolic abnormalities, and loss of mitochondrial content and function. TWEAK is a proinflammatory cytokine that binds to cell surface receptor Fn14 to activate multiple intracellular signaling pathways. We have found that the expression of Fn14 is increased in skeletal muscle of mouse models of cancer cachexia and in aged mice. Skeletal muscle-specific ablation of Fn14 inhibits muscle wasting in a murine model of cancer cachexia. TWEAK represses the rate of protein synthesis in skeletal muscle both in vivo and in vitro. Furthermore, the TWEAK-Fn14 system regulates ER stress- induced unfolded protein response (UPR) in skeletal muscle of tumor-bearing mice. In addition, our experiments demonstrate that targeted inhibition of the PERK and/or IRE1/XBP1 arms of the UPR improves protein synthesis in skeletal muscle of mice. However, the role of the TWEAK-Fn14 system and UPR pathways in the regulation of skeletal muscle mass and function during cancer cachexia and aging remains completely unknown. In this project, we will investigate the role of TWEAK/Fn14/UPR signaling axis in skeletal muscle atrophy and whether targeted genetic ablation of Fn14 or components of the UPR attenuate muscle wasting in preclinical mouse models of cancer cachexia and during aging. Based on our preliminary results, we hypothesize that the TWEAK/Fn14 system causes skeletal muscle wasting through the activation of the PERK and the IRE1α/XBP1 arms of the UPR during aging and cancer cachexia. Our specific aims are to: (I) Investigate the role of the TWEAK/Fn14 system in skeletal muscle wasting during aging and cancer cachexia, and (II) Investigate the mechanisms by which TWEAK/Fn14-induced activation of the UPR pathways cause skeletal muscle wasting during aging and cancer cachexia. Our proposed studies will identify key mechanisms responsible for the loss of skeletal muscle mass. Successful completion of this project will provide strong basis for the development of new therapies for sarcopenia and cancer cachexia.

抽象的骨骼肌消耗/恶病质是许多慢性疾病的破坏性并发症状态，例如癌症和老年人口。肌肉萎缩涉及不平衡蛋白质合成和降解的速率、功能性去神经支配、代谢异常、以及线粒体内容和功能的丧失。 TWEAK 是一种促炎细胞因子，可结合与细胞表面受体 Fn14 结合，激活多种细胞内信号通路。我们有发现癌症小鼠模型骨骼肌中 Fn14 的表达增加恶病质和老年小鼠。骨骼肌特异性消融 Fn14 可抑制肌肉萎缩癌症恶病质的小鼠模型。 TWEAK 抑制骨骼中蛋白质合成的速率体内和体外的肌肉。此外，TWEAK-Fn14 系统调节 ER 应激在荷瘤小鼠的骨骼肌中诱导未折叠蛋白反应（UPR）。此外，我们的实验表明，靶向抑制 PERK 和/或 IRE1/XBP1 臂 UPR 可改善小鼠骨骼肌中的蛋白质合成。然而， TWEAK-Fn14 系统和 UPR 通路在骨骼肌质量和功能调节中的作用癌症恶病质和衰老期间的情况仍然完全未知。在这个项目中，我们将研究 TWEAK/Fn14/UPR 信号轴在骨骼肌萎缩中的作用以及是否 Fn14 或 UPR 成分的靶向基因消融可减轻肌肉萎缩癌症恶病质和衰老过程的临床前小鼠模型。根据我们的初步结果，我们假设 TWEAK/Fn14 系统通过以下方式导致骨骼肌萎缩：衰老和癌症过程中 PERK 和 UPR 的 IRE1α/XBP1 臂的激活恶病质。我们的具体目标是： (I) 研究 TWEAK/Fn14 系统在衰老和癌症恶病质期间骨骼肌消耗，以及（II）研究其机制 TWEAK/Fn14 诱导的 UPR 通路激活导致骨骼肌萎缩在衰老和癌症恶病质期间。我们提出的研究将确定关键机制导致骨骼肌质量损失。该项目的顺利完成将为肌肉减少症和癌症恶病质新疗法的开发提供坚实的基础。