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（由适用提供）：恶病质或疾病浪费，在多种晚期疾病状态下的预后不佳，包括慢性肾脏疾病，充血性心力衰竭，癌症，艾滋病和慢性阻塞性肺部疾病。患有这种综合征的患者的特征是热量摄入量减少，瘦体重降低和基本代谢率增加，而卡路里摄入量无法纠正。七个跨膜结构域受体的黑素皮质素4受体（MC4R）在确定食物摄入和能量消耗中起着至关重要的作用。在通过其内源性逆激动剂AGRP对MC4R或药物抑制的遗传缺失或药物抑制后，恶病质动物模型受到恶病质症状的保护。 AGRP阻断了内源性MC4R激动剂，α-MSH和α-MSH介导的GαS-腺苷酸环化酶 - 训练酶训练酶信号传导途径的激活的结合。有趣的是，即使是MC4R的高亲和力合成拮抗剂，在刺激食物摄入和阻塞恶病质中也不像AGRP那样有效。最近，我们的小组发现AGRP实际上是MC4R的偏见激动剂。 AGRP与MC4R结合而不是简单地与α-MSH竞争受体占用率，而是导致向内整流钾通道KIR7.1的开放。这个发现特别有趣 鉴于AGRP的独特甲状管效应。一剂AGRP可以刺激24小时的食物摄入量长达一周。此外，施用后24小时，AGRP而不是合成的MC4R拮抗剂可能会刺激缓存小鼠的食物摄入量长达24小时。在这项研究中，我们将研究各种AGRP类似物和合成MC4R拮抗剂在细胞培养模型中耦合MC4R与KIR7.1的合成MC4R拮抗剂的等级顺序，以及刺激食物摄入和抑制疾病疾病的毒性。同样，我们将比较WT和MC4R特异性KIR7.1敲除小鼠对肿瘤缓存挑战的反应。总之，这些研究将严格检验以下假设：MC4R-KIR7.1信号传导途径对于AGRP在刺激疾病缓存和阻断疾病恶病质上的效率至关重要。如果该假设是正确的，那将又将验证一种新的药物发现路径，以开发潜在的抗纯净毒剂。