Characterization of a new pharmacological approach to cachexia

治疗恶病质的新药理学方法的表征

• 批准号: 9047987
• 负责人: Michael Litt
• 金额: $ 2.75万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9047987
• 关键词: ART protein; Acquired Immunodeficiency Syndrome; Acute; Address; Adenylate Cyclase; Affinity; Agonist; Animal Model; Animals; Appetite Stimulants; Basal metabolic rate; Binding; Biological Assay; Biological Models; Body Weight; Cachexia; Cell Culture Techniques; Chronic Kidney Failure; Chronic Obstructive Airway Disease; Congestive Heart Failure; Coupling; Cyclic AMP; Data; Development; Disease; Dose; Eating; Energy Intake; Energy Metabolism; Family; Food Energy; G Protein-Coupled Receptor Genes; Genetic; Genetic Models; Heart failure; Hospitalization; Hour; Ion Channel; Kinetics; Knockout Mice; Lead; Lewis Lung Carcinoma; Life; Ligands; MSH receptor; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Mediating; Megestrol; Melanocortin 4 Receptor; Metabolic; Modeling; Molecular; Mus; Neurons; Obesity; Patients; Peptides; Pharmaceutical Preparations; Play; Potassium Channel; Protein Binding; Publishing; Receptor Gene; Risk; Role; SHU 9119; Series; Signal Pathway; Signal Transduction; Slice; Symptoms; Syndrome; Testing; Therapeutic; Transmembrane Domain; Wasting Syndrome; advanced disease; analog; comparative; drug discovery; experience; feeding; genetic analysis; implantation; improved; interest; lean body mass; mortality; novel; outcome forecast; psychologic; public health relevance; receptor; receptor coupling; response; small molecule; tumor; wasting

 DESCRIPTION (provided by applicant): Cachexia, or disease wasting, confers a poor prognosis in a variety of advanced disease states including chronic kidney disease, congestive heart failure, cancer, AIDS, and chronic obstructive pulmonary disease. Patients afflicted by this syndrome are characterized by decreased caloric intake, decreased lean body mass and increased basal metabolic rate that cannot be corrected by increased caloric intake. The melanocortin 4 receptor (MC4R), a seven transmembrane domain receptor, plays a critical role in regulating food intake and energy expenditure. Animal models of cachexia are protected against the anorexic symptoms of cachexia following genetic deletion of the MC4R or pharmacological inhibition by its endogenous inverse agonist, AgRP. AgRP blocks binding of the endogenous MC4R agonist, α-MSH, and α-MSH mediated activation of the Gαs- adenylyl cyclase-cAMP signaling pathway. Interestingly, even high affinity synthetic antagonists of the MC4R are not as efficacious as AgRP in stimulating food intake and blocking cachexia. Recently, our group has discovered that AgRP is actually a biased agonist of the MC4R. Instead of simply competing with α-MSH for receptor occupancy, AgRP binding to MC4R leads to the opening of the inward rectifying potassium channel Kir7.1. This finding is particularly interesting given the unique orexigenic effects of AgRP. A single dose of AgRP can stimulate 24hr food intake for up to one week. Furthermore, AgRP but not synthetic MC4R antagonists can potently stimulate food intake in cachexic mice for up to 24 hours following administration. In this study we will examine the rank order of activity of a variety of AgRP analogs and synthetic MC4R antagonists in coupling the MC4R to Kir7.1 in a cell culture model, and in stimulation of food intake and inhibition of disease cachexia. Similarly, we will compare the response of WT and MC4R specific Kir7.1 knockout mice to a tumor cachexia challenge. Together, these studies will rigorously test the hypothesis that the MC4R-Kir7.1 signaling pathway is critical for the efficacy of AgRP in stimulation of feeding and blockade of disease cachexia. If this hypothesis is correct, this will, in turn, validate a novel drug discovery path for the development of potent anti-cachexigenic agents.

 描述（由申请人提供）：恶病质或疾病消耗会导致多种晚期疾病状态的预后不良，包括慢性肾病、充血性心力衰竭、癌症、艾滋病和慢性阻塞性肺病。患有这种综合征的患者的特点是热量摄入减少、去脂体重减少和基础代谢率增加，而这些不能通过增加热量摄入来纠正。黑皮质素 4 受体 (MC4R) 是一种七跨膜结构域受体，在调节食物摄入和能量消耗方面发挥着关键作用。 MC4R 基因缺失或内源性反向激动剂 AgRP 进行药理抑制后，恶病质动物模型可免受恶病质厌食症状的影响。 AgRP 阻断内源性 MC4R 激动剂 α-MSH 的结合，以及 α-MSH 介导的 Gαs-腺苷酸环化酶-cAMP 信号通路的激活。有趣的是，即使是高亲和力的合成 MC4R 拮抗剂在刺激食物摄入和阻止恶病质方面也不如 AgRP 有效。最近，我们课题组发现AgRP实际上是MC4R的偏向激动剂。 AgRP 与 MC4R 结合导致内向整流钾通道 Kir7.1 打开，而不是简单地与 α-MSH 竞争受体占据。这个发现特别有趣 鉴于 AgRP 独特的促食欲作用。单剂 AgRP 可以刺激 24 小时食物摄入量，持续长达一周。此外，AgRP（而非合成的 MC4R 拮抗剂）可以在给药后长达 24 小时内有效刺激恶病质小鼠的食物摄入。在本研究中，我们将检查多种 AgRP 类似物和合成 MC4R 拮抗剂在细胞培养模型中将 MC4R 与 Kir7.1 偶联以及刺激食物摄入和抑制疾病恶病质中的活性顺序。同样，我们将比较 WT 和 MC4R 特异性 Kir7.1 敲除小鼠对肿瘤恶病质挑战的反应。这些研究将共同​​严格检验以下假设：MC4R-Kir7.1 信号通路对于 AgRP 刺激进食和阻断疾病恶病质的功效至关重要。如果这一假设正确，这将反过来验证开发有效的抗恶病质药物的新药物发现途径。