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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）：蛋白激酶是细胞增殖、迁移和分化的重要调节因子。许多类型的癌细胞过度表达蛋白激酶。抑制特定蛋白激酶的药物现在被用于治疗一些人类癌症。抗寄生虫药物的发现几乎没有得到制药业的支持，因为这些药物的客户很穷。“替代用途”药物发现涉及对批准用于控制非寄生虫疾病的药物进行测试，以治疗寄生虫感染，这是寻找新的先导化合物的一种具有成本效益的快速途径，可以进一步研究这些先导化合物作为抗寄生虫药物。非洲人类锥虫病是由原生动物寄生虫布鲁氏锥虫引起的，需要新的药物来治疗。我们的初步生物信息学和药理学研究表明，一些蛋白激酶对布鲁氏体的生存能力很重要，可能是药物发现的目标。在Specific Aim 1中，我们将对抑制蛋白激酶的药物进行“集中筛选”，以找出哪些药物可以杀死培养中的布鲁氏杆菌的血流。有希望的抗锥虫先导化合物将在小鼠布氏体感染模型中进一步评估。在Specific Aim 2中，我们将使用亲和层析/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点。这些探索性/发育性（R21）研究的数据将为抗锥虫药物的发现提供新的先导化合物，并为未来描述布鲁氏锥虫蛋白激酶信号传导的生物学相关性奠定基础。