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 Published and unpublished data from our lab have identified the Forkhead Box (Fox) Class O protein, FoxO1, as a critical regulator of muscle wasting that is associated with cachexia in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.

项目概要/摘要恶病质的特征是进行性骨骼肌和体重减轻，影响高达 80% 癌症患者。由于肌肉质量的损失会导致虚弱，从而降低对传统疗法的耐受性治疗和死亡率增加，了解导致肌肉萎缩的机制对于开发治疗方法以改善癌症患者的生活质量并提高生存率。已发表和我们实验室未发表的数据已确定 Forkhead Box (Fox) O 类蛋白 FoxO1 是一个关键蛋白与癌症患者恶病质相关的肌肉萎缩调节剂。我们确定了转录阻遏蛋白 FoxP1，作为 FoxO1 上调的靶基因，以响应肿瘤负荷 (TBu) 的增加在肌肉萎缩之前和平行的时间点，恶病质癌的肌肉也增加患者。在初步实验中，我们发现 FoxP1 a) 可能充当关键转录的有效抑制因子参与肌肉收缩和维持肌肉完整性的因素和基因，b) 足以诱导肌纤维萎缩，c) 是 TBu 诱导肌纤维萎缩所必需的，因此暗示 FoxP1 在恶病质表型中。因此，目标 1 和 2 将检验我们的基本假设：FoxP1 就足够了诱导肌肉超微结构恶化、分解代谢途径激活和肌肉萎缩这些肿瘤诱发的肌肉病理需要其对 TBu 的反应上调。具体目标1：我们将确定FoxP1的作用并研究其分子机制足以引起肌肉萎缩。具体目标 2：建立角色并调查 FoxO1-FoxP1-MEF2c 轴驱动癌症引起的肌肉萎缩的机制。我们将测试这些假设在传统的临床前恶病质小鼠模型以及新型恶病质小鼠模型中得到了验证。癌症恶病质，其中来自胰腺导管腺癌 (PDAC) 患者的原发性切除肿瘤附着在免疫功能低下小鼠的胰腺上以创建小鼠化身。具体目标 3：确定体重的骨骼肌转录组和蛋白质组的变化在癌症恶病质的进展过程中失去 PDAC 患者及其小鼠化身。我们的第三个目标利用我们广泛获取 PDAC 患者的肌肉和肿瘤组织的优势。因此我们提出一个鉴定 PDAC 肌肉中转录组（通过 RNA-seq）和蛋白质组（通过 iTRAQ）的无偏见方法患者及其小鼠化身在恶病质进展过程中作为纵向替代对人类的研究。我们建议用肌肉组织学和超微结构来补充这些发现。我们预计目标 1 和 2 的研究结果将阐明肌肉消耗和无力的关键机制。对 TBu 的响应，而 Aim 3 中生成的数据将产生大量新知识来指导未来的预旨在预防或延缓人类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.