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Characterization of a new pharmacological approach to cachexia

治疗恶病质的新药理学方法的表征

基本信息

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
项目类别：
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

项目摘要

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.