FoxO signaling and skeletal muscle atrophy

FoxO 信号传导与骨骼肌萎缩

基本信息

批准号：
10461554
负责人：
Andrew Robert Judge
金额：
$ 1.88万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10461554
关键词：
Adult Affect Atrophic Automobile Driving Binding Body Weight Body Weight decreased Cachexia Cancer Patient Cessation of life ChIP-seq Clinical Research Complement Consensus Sequence Coupled Data Deterioration Disease Dose Down-Regulation Exhibits FOXO1A gene FOXP1 gene Frequencies Functional disorder Future Gene Expression Profile Genes Goals Histology Human Immunocompromised Host Impairment Knockout Mice Knowledge Longitudinal Studies Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Mediating Messenger RNA Molecular Mus Muscle Muscle Contraction Muscle Fibers Muscle Proteins Muscle Weakness Muscular Atrophy Myomatous neoplasm Natural regeneration Pancreas Pancreatic Ductal Adenocarcinoma Pathology Pathway interactions Patients Phenotype Physical Function Pre-Clinical Model Process Protein Isoforms Proteins Proteome Publishing Quality of life Repression Repressor Proteins Resected Respiratory Muscles Role Signal Transduction Skeletal Muscle Structure Testing Time Transcription Repressor Tumor Burden Tumor Tissue Up-Regulation Weight cancer cachexia cancer survival conventional therapy experimental study gene repression improved knock-down mortality mouse model muscle form muscle regeneration muscular structure myocyte-specific enhancer-binding-factor 2C new therapeutic target novel overexpression pancreatic cancer model pancreatic cancer patients pancreatic neoplasm pre-clinical preclinical study prevent promoter response response to injury skeletal muscle wasting therapy development transcription factor transcriptome transcriptome sequencing tumor tumor progression wasting

项目摘要

Project Summary/Abstract Cachexia is characterized by progressive skeletal muscle and body weight loss and affects up to 80% of cancer patients. Since this loss of muscle mass contributes to weakness, reduced tolerance to conventional treatments, and increased mortality, understanding the mechanisms that drive muscle wasting is critical to the development of treatments to improve quality of life and enhance survival of cancer patients. Published and unpublished data from our lab have identified the Forkhead Box (Fox) Class O protein, FoxO1, as a critical regulator of muscle wasting that is associated with cachexia in cancer patients. We identified the transcriptional repressor, FoxP1, as a target gene upregulated by FoxO1 in response to tumor burden (TBu) that is increased at time points which precede and parallel muscle wasting and is also increased in muscle of cachectic cancer patients. In preliminary experiments we found that FoxP1 a) may act as a potent repressor of key transcription factors and genes involved in muscle contraction and the maintenance of muscle integrity, b) is sufficient to induce muscle fiber atrophy and c) is required for muscle fiber atrophy induced by TBu, thus implicating FoxP1 in the cachectic phenotype. Aims 1 and 2 will therefore test our underlying hypothesis that FoxP1 is sufficient to induce deterioration of muscle ultrastructure, activation of catabolic pathways, and muscle atrophy and weakness and that its upregulation in response to TBu is required for these tumor-induced muscle pathologies. Specific Aim 1: We will establish the role and investigate the molecular mechanisms by which FoxP1 is sufficient to induce muscle wasting. Specific Aim 2: To establish the role and investigate the mechanisms by which a FoxO1-FoxP1-MEF2c axis drives cancer-induced muscle wasting. We will test these hypotheses in a conventional pre-clinical mouse model of cachexia as well as in a novel mouse model of cancer cachexia in which primary resected tumors from pancreatic ductal adenocarcinoma (PDAC) patients are attached to the pancreas of immunocompromised mice to create mouse avatars. Specific Aim 3: To identify changes in the skeletal muscle transcriptome and proteome of weight losing PDAC patients and their mouse avatars during the progression of cancer cachexia. Our third aim takes advantage of our wide access to muscle and tumor tissue from PDAC patients. We thus propose an unbiased approach to identify the transcriptome (via RNA-seq) and proteome (via iTRAQ) in muscle of PDAC patients as well as their mouse avatars during the progression of cachexia as a surrogate for longitudinal studies in humans. We propose to complement these findings with muscle histology and ultrastructure. We anticipate that our findings from Aims 1 and 2 will elucidate key mechanisms of wasting and weakness in response to TBu, while data generated in Aim 3 will generate a plethora of new knowledge to guide future pre- clinical and clinical studies aimed at preventing or retarding cancer-induced cachexia in the human condition.

项目摘要/摘要缓存的特征是进行性骨骼肌和体重减轻，并影响多达80％癌症患者。由于这种肌肉质量的损失导致弱点，因此对常规的容忍度降低了治疗和死亡率增加，了解驱动肌肉浪费的机制对开发治疗以改善生活质量并提高癌症患者的生存率。出版和来自我们实验室的未发表的数据已将叉子盒（FOX）o蛋白foxo1确定为关键与癌症患者的恶病质有关的肌肉浪费的调节剂。我们确定了转录阻遏物，FOXP1，作为响应肿瘤负担（TBU）的靶基因，被FOXO1上调了在缓存癌症肌肉之前和平行肌肉之前的时间点上也有所增加患者。在初步实验中，我们发现FOXP1 a）可以充当钥匙转录的有效阻遏物肌肉收缩涉及的因素和基因，肌肉完整性的维持，b）足以 TBU诱导的肌肉纤维萎缩需要诱导肌肉纤维萎缩，C）牵涉到FOXP1 在缓存表型中。因此，目标1和2将检验我们的基本假设，即FOXP1就足够了诱导肌肉超微结构的恶化，分解代谢途径的激活以及肌肉萎缩和这些肿瘤诱导的肌肉病理学需要弱点，并且需要对TBU的上调。具体目的1：我们将确定作用并研究FOXP1的分子机制足以诱导肌肉浪费。特定目的2：确定角色并调查 FOXO1-FOXP1-MEF2C轴驱动癌症引起的肌肉浪费的机制。我们将测试这些假设在常规的临床前小鼠模型以及新型的小鼠模型中癌症恶病质，其中原发性切除的胰腺导管腺癌（PDAC）患者的肿瘤附着在免疫功能低下的小鼠的胰腺上，以创建小鼠头像。特定目标3：确定骨骼肌转录组和重量蛋白质组的变化在癌症恶病质进展过程中，失去PDAC患者及其小鼠头像。我们的第三个目标利用我们从PDAC患者获得肌肉和肿瘤组织的广泛机会。因此，我们提出了一个识别PDAC肌肉中的转录组（通过RNA-Seq）和蛋白质组（通过ITRAQ）的无偏方法在恶病质的进展过程中，患者以及其小鼠头像作为纵向的替代人类的研究。我们建议将这些发现与肌肉组织学和超微结构相辅相成。我们预计我们来自目标1和2的发现将阐明浪费和无力的关键机制对TBU的响应，尽管AIM 3中产生的数据将产生大量的新知识，以指导未来旨在预防或阻碍人类病情癌症引起的恶病质的临床和临床研究。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Low Muscle Mass and Radiodensity Associate with Impaired Pulmonary Function and Respiratory Complications in Patients with Esophageal Cancer.

低肌肉质量和放射密度与食管癌患者的肺功能受损和呼吸系统并发症相关。

DOI：
10.1097/xcs.0000000000000535
发表时间：
2023
期刊：
Journal of the American College of Surgeons
影响因子：
5.2
作者：
Cameron,MilesE;Ayzengart,AlexanderL;Oduntan,Olusola;Judge,SarahM;Judge,AndrewR;Awad,ZiadT
通讯作者：
Awad,ZiadT

Osteopenia is associated with wasting in pancreatic adenocarcinoma and predicts survival after surgery.

DOI：
10.1002/cam4.4416
发表时间：
2022-01
期刊：
Cancer medicine
影响因子：
4
作者：
Cameron ME;Underwood PW;Williams IE;George TJ;Judge SM;Yarrow JF;Trevino JG;Judge AR
通讯作者：
Judge AR

Blocking muscle wasting via deletion of the muscle-specific E3 ligase MuRF1 impedes pancreatic tumor growth.

DOI：
10.1038/s42003-023-04902-2
发表时间：
2023-05-13
期刊：
COMMUNICATIONS BIOLOGY
影响因子：
5.9
作者：
Neyroud, Daria;Laitano, Orlando;Dasgupta, Aneesha;Lopez, Christopher;Schmitt, Rebecca E.;Schneider, Jessica Z.;Hammers, David W.;Sweeney, H. Lee;Walter, Glenn A.;Doles, Jason;Judge, Sarah M.;Judge, Andrew R.
通讯作者：
Judge, Andrew R.