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 病原体是一种衰弱的综合征，导致由于骨骼耗尽而导致严重的非自愿体重减轻 肌肉和脂肪组织。该综合征发生在大多数癌症中，大约有助于 所有癌症死亡中的第三。目前，尚无有效的疗法来抗击这种恶性疾病。用于胰腺 导管腺癌（PDAC）是胰腺癌最具侵略性的形式，有效的潜在益处 由于其中85％ 患者平均会损失其罚款前体重的14％，而恶病质大大限制了他们的耐受能力 手术，化学或放射疗法。新疗法可能会从对 导致肌肉浪费和肿瘤发育的机制（恶病质的主要驱动力）。这个程序 项目汇集了骨骼肌，肿瘤学，免疫学和卡赫西亚的专家研究人员，以探索 在癌症cachexia的宏观环境中，NF-B/IL-6/STAT3信号轴的作用 - 考虑两者 肌肉丧失的机制和PDAC的发展。在该计划的项目2中，将重点放在 该信号轴的NF-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相关联于肌肉的修复练习 纤维。 NF-B在干细胞中被激活，并在阻塞修复和促进肌肉浪费的功能 调节局部肌肉炎症状况。第二个发现提供了有关NF-B的见解 PDAC发育过程中肿瘤细胞内的功能。使用胰腺癌的小鼠模型，我们 表明NF-B在保护肿瘤细胞免受抗肿瘤的监测特性中起关键作用 巨噬细胞和细胞毒性T细胞。 NF-B能够通过 调节免疫抑制性细胞因子GDF15。该项目的目的是探讨以下假设 NF-B通过在肌肉干细胞中作用以阻断肌肉的作用在癌症恶病质的宏观环境中起作用 修复以及通过生产免疫抑制基因（例如GDF-15）来促进PDAC。 为了实现这一目标，我们试图执行以下两个具体目标：1）确定NF-B的相关性 调节癌症恶病质肌肉感染； 2）确定GDF-15和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以及该信号分量如何与IL-6和STAT3相交以调节肌肉浪费和肿瘤 癌症恶病质宏观环境内的发展。