Project 2 NF-#B regulation in muscle wasting and pancreatic cancer-induced cachexia

项目2 NF-

• 批准号: 10172470
• 负责人: Denis C Guttridge
• 金额: $ 44.59万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10172470
• 关键词: Adipose tissue; Body Weight; Body Weight decreased; Cachexia; Cancer Patient; Cessation of life; Cytotoxic T-Lymphocytes; Data; Development; Disease; Eating; Fatigue; GDF15 gene; Genes; Goals; Human body; Immune; Immunologic Surveillance; Immunology; Incidence; Individual; Inflammation; Inflammation Mediators; Inflammatory; Interleukin-6; Knowledge; Laboratories; Ligands; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Morbidity - disease rate; Mus; Muscle; Muscle Fibers; Muscle satellite cell; Muscular Atrophy; Myomatous neoplasm; Natural Immunity; Oncology; Operative Surgical Procedures; Pancreatic Ductal Adenocarcinoma; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Play; Production; Program Research Project Grants; Property; Publishing; Quality of life; Radiation therapy; Registries; Regulation; Reporting; Research; Research Personnel; Risk; Role; STAT3 gene; Signal Pathway; Signal Transduction; Skeletal Muscle; Survival Rate; Syndrome; T-Lymphocyte; Testing; Tissues; Transcription Coactivator; Tumor-infiltrating immune cells; Weight; adaptive immunity; adverse outcome; anticancer treatment; base; cancer cachexia; chemotherapy; combat; cytokine; effective therapy; immunoregulation; improved; inflammatory milieu; insight; macrophage; mortality; mouse model; muscle form; neoplastic cell; novel; novel therapeutics; pancreas development; pancreatic cancer model; pancreatic cancer patients; prevent; progenitor; programs; repaired; response; skeletal muscle wasting; stem cell function; stem cells; transcription factor; tumor

PROJECT SUMMARY: PROJECT 2 Cachexia is a debilitating syndrome that results in severe, involuntary weight loss due to the depletion of skeletal muscle and adipose tissues. This syndrome occurs in a majority of cancers and contributes to approximately a third of all cancer deaths. Currently, no effective therapy exists to combat this malignant disorder. For pancreatic ductal adenocarcinoma (PDAC), the most aggressive formof pancreatic cancer, the potential benefit for effective cachexia therapies may be even greater than for other cachexia-associated malignancies, since 85% of these patients lose on average 14% of their pre-illness weight, and cachexia dramatically limits their ability to tolerate surgery, chemo- or radiotherapy. New therapies will likely evolve from an enhanced understanding of the mechanisms leading to muscle wasting and tumor development (the primary driver of cachexia). This program project brings together expert investigators in skeletal muscle, oncology, immunology, and cachexia, to explore the role an NF-B/IL-6/STAT3 signaling axis within the macroenvironment of cancer cachexia – considering both mechanisms of muscle loss and the development of PDAC. In Project 2 of this program, focus will be placed on the NF-B portion of this signaling axis. Recent efforts have centered on two new concepts. The first is that cancer cachexia associates with the activation of muscle stem cells initiating a repair pr ocess on the muscle fiber. NF-B is activated in stem cells, and functions to block repair and promote muscle wasting through the regulation of a local muscle inflammatory condition. The second discovery provides insight in how NF-B functions within the tumor cell during development of PDAC. Using a mouse model of pancreatic cancer, we showed that NF-B plays a critical role in protecting tumor cells from the surveillance property of anti-tumor macrophages and cytotoxic T cells. NF-B is able to suppress both innate and adaptive immunity through the regulation of the immunosuppressive cytokine, GDF15. The goal of this project is to explore the hypothesis that NF-B functions in the macroenvironment of cancer cachexia by acting in muscle stem cells to block muscle repair, as well as promoting PDAC through the production of immunosuppressive genes such as GDF-15. Towards this goal we seek to perform the following two specific aims: 1) Determine the relevance of NF-B regulation of muscle inflammation in cancer cachexia; and 2) Determine how NF-B regulation of GDF-15 and immune modulation promotes PDAC. Achieving this goal will enhance our understanding of the relevance of NF- B and how this signaling component intersects with IL-6 and STAT3 to regulate muscle wasting and tumor development within the macroenvironment of cancer cachexia.

项目概要：项目2 恶病质是一种使人衰弱的综合征，其由于骨骼肌的消耗而导致严重的、不自主的体重减轻。 肌肉和脂肪组织。这种综合征发生在大多数癌症中，并导致大约 三分之一的癌症死亡。目前，没有有效的治疗方法来对抗这种恶性疾病。胰腺 导管腺癌（PDAC）是胰腺癌最具侵袭性的形式， 恶病质治疗可能甚至比其他恶病质相关恶性肿瘤更好，因为85%的恶病质相关恶性肿瘤 患者平均体重减轻14%，恶病质极大地限制了他们的耐受能力。 手术、化疗或放疗。新的治疗方法可能会从增强对癌症的理解中发展出来。 导致肌肉萎缩和肿瘤发展的机制（恶病质的主要驱动因素）。这个程序 该项目汇集了骨骼肌、肿瘤学、免疫学和恶病质方面的专家研究人员， NF-κ B B/IL-6/STAT 3信号轴在癌症恶病质宏观环境中的作用-考虑到两者 肌肉损失的机制和PDAC的发展。在该计划的项目2中，重点将放在 NF-κ B位于这个信号轴的B部分。最近的努力集中在两个新概念上。首先是 癌症恶病质与肌肉干细胞的激活有关， 光纤NF-κ B B在干细胞中被激活，并通过免疫抑制来阻断修复和促进肌肉萎缩。 调节局部肌肉炎症状态。第二个发现提供了NF-κ B B 在PDAC的发展过程中在肿瘤细胞内起作用。使用胰腺癌小鼠模型，我们 表明NF-κ B B在保护肿瘤细胞免受抗肿瘤药物的监视作用中起关键作用 巨噬细胞和细胞毒性T细胞。NF-κ B B能够通过免疫抑制剂抑制先天性和适应性免疫。 免疫抑制细胞因子GDF 15的调节。这个项目的目标是探索假设， NF-κ B B在癌症恶病质的大环境中通过作用于肌肉干细胞来阻断肌肉 修复，以及通过产生免疫抑制基因如GDF-15来促进PDAC。 为了实现这一目标，我们寻求执行以下两个具体目标：1）确定NF-κ B B的相关性 癌症恶病质中肌肉炎症的调节;和2）确定NF-κ B B如何调节GDF-15和 免疫调节促进PDAC。实现这一目标将增强我们对NF相关性的理解- IL B以及这种信号传导成分如何与IL-6和STAT 3交叉以调节肌肉萎缩和肿瘤 癌症恶病质的宏观环境内的发展。