PQ6: Therapeutic approaches for autonomic and neuroendocrine dysfunction in cancer cachexia

PQ6：癌症恶病质自主神经和神经内分泌功能障碍的治疗方法

• 批准号: 10700965
• 负责人: Aaron Grossberg
• 金额: $ 42.41万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-10 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700965
• 关键词: Acute; Adipose tissue; Adrenergic Agents; Adrenergic Receptor; Animals; Anorexia; Atrophic; Attenuated; Behavior; Behavioral; Body Weight decreased; Cachexia; Cancer Patient; Cardiac; Cardiovascular system; Catabolism; Chronic; Chronic Disease; Chronic stress; Clinical Trials Design; Collaborations; Corticosterone; Corticotropin-Releasing Hormone; Data; Dedications; Disease; Energy Metabolism; Evolution; Exhibits; Fatigue; Functional disorder; Genetic; Glucocorticoids; Goals; Human; Hypothalamic structure; Impairment; Inflammatory; Intervention; Laboratories; Lethargies; Life; Malignant Neoplasms; Metabolic; Metabolic dysfunction; Metabolic syndrome; Metabolism; Modeling; Morbidity - disease rate; Motivation; Mus; Muscle; Muscular Atrophy; Nerve; Neuroendocrinology; Neurons; Neurosecretory Systems; Neurotransmitters; Norepinephrine; Observational Study; Organ; Organism; Output; Pancreatic Ductal Adenocarcinoma; Pathologic; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Phase II Clinical Trials; Phenotype; Physical Function; Physiological; Plasma; Pre-Clinical Model; Prevention; Quality of life; Reagent; Research; Role; Sick Role; Signal Transduction; Skeletal Muscle; Stress; Sympathetic Nervous System; Systemic disease; Testing; Therapeutic; Therapeutic Intervention; Tissues; acute stress; behavioral phenotyping; behavioral response; biological adaptation to stress; cancer cachexia; cancer type; clinical translation; defined contribution; density; design; exercise intolerance; experience; functional decline; hypothalamic-pituitary-adrenal axis; metabolic phenotype; mortality risk; mouse model; neuroinflammation; new therapeutic target; novel; novel therapeutics; pancreatic cancer patients; pancreatic ductal adenocarcinoma model; pharmacologic; prospective; response; synergism; systemic inflammatory response; therapeutically effective; tumor; tumor growth; wasting

Project Summary: Illness behaviors, metabolic disturbances, and cardiovascular compromise are common in patients with chronic systemic diseases, and contribute substantially to quality of life and ultimate survival. Other illness- induced morbidities including anorexia and lethargy also compromise the ability of patients to recover from life- saving or extending interventions, and diminish the motivational drive to aggressively battle the underlying condition. Although cachexia in cancer patients was described more than two thousand years ago, the central mechanisms underlying this disorder are poorly understood. Furthermore, there is currently no effective pharmaceutical treatment. Cardiovascular impairment is common in all chronic diseases, and can be a presenting complaint in cancer patients, even prior to initiation of therapy. Our laboratory is dedicated to unraveling the basic mechanisms whereby cancer triggers neuroinflammation and subsequent chronic activation of systemic stress responses in patients with cancer. In this proposal, we will focus on understanding the scope and mechanism by which systemic illness induces chronic activation and alteration in the sympathetic nervous system. The significance of this proposal resides in its unique combination of our historical focus on neuroendocrinology and neuroinflammation, with new collaborations and efforts directed at understanding the extent and mechanisms of cardiovascular impairment and sympathetic nervous system plasticity in patients with cancer. The long-term goal of our research is to gain mechanistic understanding of the acute illness response and how it is transitioned into chronic neuroinflammation in all cancer types, in order to develop more effective therapeutic interventions.

项目总结： 疾病行为、代谢紊乱和心血管损害在慢性阻塞性肺疾病患者中很常见 慢性系统性疾病，并对生活质量和最终生存作出重大贡献。其他疾病- 包括厌食症和嗜睡在内的诱发性疾病也会损害患者从生活中恢复的能力-- 节省或延长干预措施，并降低与潜在疾病作斗争的动机 条件。尽管癌症患者的恶病质在两千多年前就被描述出来了，但中央 这种疾病背后的机制还知之甚少。此外，目前还没有有效的 药物治疗。心血管损害在所有慢性病中都很常见，而且可能是一种 在癌症患者中提出抱怨，甚至在开始治疗之前。我们的实验室致力于 解开癌症引发神经炎症和随后的慢性炎症的基本机制 癌症患者全身应激反应的激活。在这份提案中，我们将重点了解 全身性疾病引起的慢性激活和改变的范围和机制 交感神经系统。这项提议的意义在于它将我们的 历史上对神经内分泌学和神经炎症的关注，以及针对以下方面的新合作和努力 了解心血管损害和交感神经系统损害的程度和机制 癌症患者的可塑性。我们研究的长期目标是从机制上理解 在所有癌症类型中，急性疾病反应以及它如何转变为慢性神经炎，依次为 以开发更有效的治疗干预措施。