Protein Kinases of a Trypanosome

锥虫的蛋白激酶

基本信息

批准号：
7524058
负责人：
KOJO A. MENSA-WILMOT
金额：
$ 18.47万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-22 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7524058
关键词：
AEE 788 Affect Affinity Chromatography African Trypanosomiasis Antineoplastic Agents Bioinformatics Biological Blood Blood Circulation Canertinib Cell Proliferation Chemicals Client Data Development Disease Drug Delivery Systems Drug Industry Epidermal Growth Factor Receptor Erlotinib Foundations Future Gene Expression Human Infection Lead Malignant Neoplasms Modeling Molecular Genetics Mus Parasites Parasitic Diseases Patients Pharmaceutical Preparations Pharmacologic Substance Phosphorylation Phosphotransferases Preclinical Drug Evaluation Predisposition Protein Kinase Protein Kinase Inhibitors Proteins Proteomics Role Route Signal Transduction Stream Testing Trypanosoma Trypanosoma brucei brucei Work base cancer cell cost cost effective drug discovery drug testing genome sequencing inhibitor/antagonist killings migration mouse model novel protein kinase inhibitor public health relevance theories

项目摘要

DESCRIPTION (provided by applicant): Protein kinases are important regulators of cell proliferation, migration, and differentiation. Cancer cells of many types over-express protein kinases. Drugs that inhibit specific protein kinases are now used to treat some human cancers. Anti-parasite drug discovery receives almost no support from the pharmaceutical industry, because the clients for the drugs are poor. "Alternative Use" drug discovery, which involves testing of drugs approved for control of non-parasitic diseases as treatment for parasite infections is a cost-effective and fast route for finding new lead compounds that may be studied further as anti-parasite drugs. Novel drugs are needed for treatment of human African trypanosomiasis, which is caused by the protozoan parasite Trypanosoma brucei. Our preliminary bioinformatic and pharmacological studies indicate that some protein kinases are important for viability and may be targeted for drug discovery in T. brucei. In Specific Aim 1, we will perform a "focused screen" of drugs that inhibit protein kinases to find out which of them kill blood stream form T. brucei in culture. Promising anti-trypanosome lead compounds will be evaluated further in a mouse model of T. brucei infection. In Specific Aim 2, we will validate the target of the protein kinase inhibitors, using a combination of affinity chromatography/chemical proteomics and molecular genetics approaches. Data from these exploratory/developmental (R21) studies will provide new lead compounds for anti-trypanosome drug discovery, and form the basis for a future work to delineate the biological relevance of protein kinase signaling in T. brucei. PUBLIC HEALTH RELEVANCE: Trypanosomes cause diseases that affect millions of people world-wide. Work described in this proposal may lead to discovery of new drugs for treatment of human African trypanosomiasis.

描述（由申请人提供）：蛋白质激酶是细胞增殖，迁移和分化的重要调节剂。多种过表达蛋白激酶的癌细胞。抑制特异性蛋白激酶的药物现在用于治疗某些人类癌症。抗寄生虫的药物发现几乎没有制药行业的支持，因为药物的客户很差。 “替代用途”药物发现，涉及测试批准控制非寄生虫病作为寄生虫感染的药物，是寻找新铅化合物的成本效益且快速的途径，可以进一步研究，这些化合物可以作为抗寄生虫药物进行进一步研究。需要新的药物来治疗非洲锥虫病，这是由原生动物寄生虫锥虫引起的。我们的初步生物信息学和药理学研究表明，某些蛋白激酶对于生存能力很重要，并且可能是针对布鲁氏菌的药物发现的。在特定的目标1中，我们将对抑制蛋白激酶的药物进行“聚焦筛查”，以找出哪些杀死了培养物中的t菌血流。有希望的抗肌体铅化合物将在t. brucei感染的小鼠模型中进一步评估。在特定目标2中，我们将使用亲和色谱/化学蛋白质组学和分子遗传学方法的组合来验证蛋白激酶抑制剂的靶标。这些探索/发育研究（R21）研究的数据将为抗肌体药物发现提供新的铅化合物，并构成了未来工作的基础，以描绘布鲁西t。brucei中蛋白激酶信号的生物学相关性。公共卫生相关性：锥虫引起的疾病会影响全球数百万的人。该提案中描述的工作可能导致发现新药治疗人类非洲锥虫病。