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: 9177690
• 负责人: Michael Litt
• 金额: $ 4.14万
• 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/9177690
• 关键词: ART protein; Acquired Immunodeficiency Syndrome; Acute; Address; Adenylate Cyclase; Affinity; Agonist; Alpha Cell; Animal Model; Animals; Anticachexia Agent; Appetite Stimulants; Basal metabolic rate; Binding; Binding Proteins; 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 Receptors; GTP-Binding Protein alpha Subunits, Gs; Genetic; Genetic Models; Heart failure; Hospitalization; Hour; Ion Channel; Kinetics; Knockout Mice; Lead; Lewis Lung Carcinoma; Ligands; LoxP-flanked allele; MSH receptor; Malignant Epithelial Cell; Malignant Neoplasms; Measures; Mediating; Megestrol; Melanocortin 4 Receptor; Metabolic; Modeling; Molecular; Mus; Neurons; Obesity; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Play; Potassium Channel; Publishing; Receptor Gene; Risk; Role; SHU 9119; Series; Signal Pathway; Signal Transduction; Slice; Symptoms; Syndrome; Testing; Therapeutic; Thinness; Transmembrane Domain; Wasting Syndrome; advanced disease; alpha-Melanocyte stimulating hormone; analog; comparative; drug discovery; experience; feeding; genetic analysis; implantation; improved; inward rectifier potassium channel; lean body mass; mortality; novel therapeutics; outcome forecast; protein function; 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(申请人提供)：恶病质，或疾病消瘦，在各种晚期疾病状态下，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病，预后不良。患有这种综合征的患者的特点是卡路里摄入量减少，瘦体重减少，基础代谢率增加，这些不能通过增加卡路里摄入量来纠正。黑素皮质素4受体(MC4R)是一种7个跨膜区的受体，在调节食物摄入和能量消耗方面起着关键作用。恶病质的动物模型可以预防因MC4R基因缺失或其内源性反向激动剂AgRP的药理抑制而出现的恶病质厌食症状。银杏叶提取物阻断内源性MC4R激动剂α-mSh的结合，并阻断α-msh介导的G-αS-腺酰环化酶-cAMP信号通路的激活。有趣的是，即使是高亲和力的MC4R合成拮抗剂，在刺激食物摄入和阻止恶病质方面也不如AgRP有效。最近，我们的研究小组发现，AgRP实际上是MC4R的一种有偏见的激动剂。而不是简单地与α-MSH竞争受体占有率，与MC4R结合导致开放内向整流钾通道Kir7.1。这一发现特别有趣。 鉴于AgRP独特的促食欲作用。单剂AgRP可以刺激24小时的食物摄入量，最长可达一周。此外，AgRP而不是合成的MC4R拮抗剂可以有效地刺激恶病质小鼠在给药后长达24小时的食物摄取。在这项研究中，我们将检查各种AgRP类似物和合成的MC4R拮抗剂在细胞培养模型中将MC4R偶联到Kir7.1上，以及在刺激食物摄入和抑制疾病恶病质方面的活性排序。同样，我们将比较WT和MC4R特异性Kir7.1基因敲除小鼠对肿瘤恶病质挑战的反应。总之，这些研究将严格检验这一假设，即MC4R-Kir7.1信号通路对于AgRP刺激摄食和阻断疾病恶病质的疗效至关重要。如果这一假设是正确的，这将反过来验证开发有效的抗恶病质药物的一条新的药物发现途径。