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.

项目摘要：项目 2 恶病质是一种使人衰弱的综合征，由于骨骼消耗而导致严重的、非自愿的体重减轻 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 占所有癌症死亡人数的三分之一。目前，尚无有效的疗法来对抗这种恶性疾病。对于胰腺 导管腺癌（PDAC）是胰腺癌中最具侵袭性的一种形式，有效治疗的潜在益处 恶病质治疗可能比其他恶病质相关恶性肿瘤更有效，因为其中 85% 患者体重平均比病前减轻 14%，恶病质严重限制了他们的耐受能力 手术、化疗或放疗。新的疗法可能会随着对疾病的进一步了解而发展 导致肌肉萎缩和肿瘤发展的机制（恶病质的主要驱动因素）。这个节目 该项目汇集了骨骼肌、肿瘤学、免疫学和恶病质领域的专家研究人员，以探索 NF-κB/IL-6/STAT3 信号轴在癌症恶病质宏观环境中的作用 – 考虑两者 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 该信号轴的 NF-β 部分。最近的努力集中在两个新概念上。第一个是 癌症恶病质与肌肉干细胞的激活有关，启动肌肉的修复过程 纤维。 NF-κB 在干细胞中被激活，并通过以下方式阻止修复并促进肌肉萎缩： 调节局部肌肉炎症状况。第二个发现提供了关于 NF-κB 如何 PDAC 发育过程中肿瘤细胞内的功能。使用胰腺癌小鼠模型，我们 研究表明 NF-κB 在保护肿瘤细胞免受抗肿瘤药物的监视方面发挥着关键作用 巨噬细胞和细胞毒性 T 细胞。 NF-β能够通过抑制先天性和适应性免疫 免疫抑制细胞因子 GDF15 的调节。该项目的目标是探索以下假设： NF-κB 通过作用于肌肉干细胞来阻断肌肉，从而在癌症恶病质的大环境中发挥作用 修复，以及通过产生 GDF-15 等免疫抑制基因来促进 PDAC。 为了实现这一目标，我们寻求实现以下两个具体目标：1）确定 NF-β 的相关性 癌症恶病质中肌肉炎症的调节； 2) 确定 NF-κB 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 B 以及该信号传导成分如何与 IL-6 和 STAT3 相互作用来调节肌肉萎缩和肿瘤 癌症恶病质宏观环境中的发展。