Exploiting the cAMP pathway in Chagas Disease Therapy

在恰加斯病治疗中利用 cAMP 通路

• 批准号: 8147474
• 负责人: DANIEL L ALTSCHULER
• 金额: $ 6.59万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-19 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8147474
• 关键词: Affinity; Americas; Area; Argentina; Attention; Award; Benznidazole; Binding; Biochemical; Bioinformatics; Biology; Cell Cycle; Cell Cycle Stage; Cells; Cessation of life; Chagas Disease; Collaborations; Computer Simulation; Country; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Developed Countries; Development; Disease; Dominant-Negative Mutation; Drug Design; Effectiveness; Environment; Event; Future; Gene Targeting; Genome; Goals; Grant; Health; Human; Institution; International; Intervention; Invaded; Laboratories; Latin America; Life; Mammalian Cell; Nifurtimox; Nomads; Parasites; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Play; Population; Principal Investigator; Process; Public Health; Reagent; Research; Role; Rural Population; Scientist; Signal Pathway; Signal Transduction; South America; Testing; Toxic effect; Trypanosoma cruzi; Universities; Vaccines; Validation; adenosine cyclic-3' ,5' -monophosphate binding proteins; alternative treatment; analog; base; design; expression cloning; inhibitor/antagonist; insight; migration; novel; parent grant; phosphoric diester hydrolase; rural area; tool

DESCRIPTION (provided by applicant): This Fogarty International Research Collaboration Award (FIRCA) application, based on parent grant R01 CA071649-11 (Principal Investigator Altschuler, Daniel), was designed to expand the research capacity of the foreign scientist (Dr. Martin Edreira) and institution (Universidad de Buenos Aires, Buenos Aires, Argentina), exploiting the cAMP signaling pathway in search of a potential target to a global public health illness, i.e. Chagas disease. Chagas disease is a life-threatening illness caused by the protozoan parasite Trypanosoma cruzi. Endemic to poor rural areas of South America, with an infected population estimated in 10 million and an alarming 25,000 deaths per year, its impact is becoming global due to migration to developed countries; estimates indicate that around 300,000 infected migrants currently live in the US. No vaccines are available, and drugs introduced in the early 1970's, i.e. nifurtimox and benznidazole, represent the only currently available options for treatment. These anti-parasitic drugs, however, show limited efficacy and high toxicity. Thus, the development of novel alternative treatments is urgently needed. Roles for cAMP-dependent signaling pathways, both in the parasite and the host mammalian cell, are well established as modulators of T. cruzi's cell cycle and its ability to invade the host. Although much attention is focused on the putative machinery involved in synthesis (i.e. cyclase) and degradation (i.e. phosphodiesterase) of cAMP, the role of potential new cAMP effector pathways is currently unknown. The goal of the parental grant was the identification and characterization of new PKA-independent cAMP effector pathways in mammalian cells, as well as the development of specific reagents for their analysis. The general hypothesis to be tested in this application is that, similarly to mammalian cells, multiple cAMP effector pathways might play significant roles in the pathogenic mechanisms used by this human parasite. Two specific aims are proposed to approach this: Sp. Aim 1: To identify and characterize new cAMP effectors in T. cruzi, and Sp. Aim 2: To determine the role of specific mammalian cAMP effectors during host invasion. Successful completion of the proposed aims has the potential to uncover new aspects of cAMP biology and to provide new insights into the mechanisms of pathogenesis involved in Chagas disease. Although most of the studies will be performed by Dr. Edreira at the Universidad of Buenos Aires in Argentina, all the tools generated or currently in process from the parent grant at the University of Pittsburgh will be readily available for Dr. Edreira's research. The close collaboration between laboratories with strong expertise in cAMP biology and Chagas research should provide a productive environment that will potentially advance the field of T. cruzi biology, its interaction with the host cell and holds promise of identifying new and unique target/s for future intervention. PUBLIC HEALTH RELEVANCE: Chagas is a potentially life-threatening disease caused by the protozoan parasite, Trypanosoma cruzi. Endemic to the Americas, it represents a serious health threat among people living in poor rural populations in Latin America. Available anti-parasitic drugs have limited effectiveness and are highly toxic. For this reason, there is an urgent need for new treatments, implying the identification of new potential targets and the design of novel drugs for anti-trypanosomal therapy. cAMP pathways, involved in T. cruzi proliferation, differentiation and invasion, are essential for the parasite and could be targets for new drugs. The overall aim of the application focused on the characterization of effector interactions within the cAMP pathway involved in Trypanosoma cruzi biology and in host cell during invasion, in order, to identify specific key players to be use as targets for drug design. The studies proposed should provide new insights into cAMP-dependent signaling events. Unraveling the mechanisms underlying these new interactions might provide insights into the rational design of new specific inhibitors with effector pathway selectivity that might have implications in the development of new therapies for Chagas disease.

描述（由申请人提供）：基于父母的Fogarty国际研究合作奖（FIRCA）申请，基于父母授予R01 CA071649-11（首席研究员Altschuler，Daniel），旨在扩大外交科学家（Martin Edreira博士）的研究能力全球公共卫生疾病，即查加斯病。 Chagas病是一种由原生动物寄生虫锥虫引起的威胁生命的疾病。南美贫穷的农村地区的特有，感染人口估计为1000万，每年有25,000人死亡，由于向发达国家的移民，其影响正在全球化；估计表明，目前约有30万受感染的移民居住在美国。没有疫苗可用，在1970年代初期引入的药物，即nifurtimox和苯甲酸唑，代表了当前唯一可用的治疗选择。然而，这些抗寄生虫的功效有限和毒性高。因此，迫切需要开发新的替代疗法。在寄生虫和宿主哺乳动物细胞中，依赖CAMP依赖性信号通路的角色已成为Cruzi细胞周期的调节剂及其入侵宿主的能力。尽管非常关注集中在cAMP的合成（即环酶）和降解（即磷酸二酯酶）中的推定机械上，但目前未知潜在的新cAMP效应途径的作用。父母赠款的目的是鉴定和表征哺乳动物细胞中新型PKA独立的cAMP效应子途径，以及开发特定试剂进行分析。在此应用中要检验的一般假设是，与哺乳动物细胞类似，多个cAMP效应途径可能在该人寄生虫使用的致病机制中起着重要作用。提出了两个具体的目标来解决此问题：sp。目标1：识别和表征T. Cruzi和Sp。目标2：确定在宿主入侵期间特定的哺乳动物营地效应子的作用。成功完成拟议的目标有可能发现camp生物学的新方面，并提供有关chagas病发病机理机制的新见解。尽管大多数研究都将由阿根廷布宜诺斯艾利斯大学的埃德雷拉（Edreira）博士进行，但匹兹堡大学的父母赠款生成或目前正在处理的所有工具都将随时可用于Edreira博士的研究。实验室之间具有强大专业知识在CAMP生物学和Chagas Research的实验室之间的密切合作应提供一个富有成效的环境，该环境将有可能发展Cruzi Biology领域，与宿主细胞的相互作用，并有望确定新的和独特的目标，以进行未来的干预。 公共卫生相关性：Chagas是一种潜在的威胁生命的疾病，由原生动物寄生虫Cruzi引起。在美洲的地方，它代表着在拉丁美洲贫困农村人口中生活的人们的严重健康威胁。可用的抗寄生虫有效性有限，剧毒剧烈。因此，迫切需要新的治疗方法，这意味着鉴定出新的潜在靶标以及针对抗肌体疗法的新型药物的设计。参与克鲁氏杆菌增殖，分化和侵袭的营地对于寄生虫至关重要，可能是新药的靶标。应用程序的总体目的集中在crypanosoma cruzi生物学涉及的营地途径和入侵期间宿主细胞中的效应子相互作用的表征，以确定要用作药物设计目标的特定关键参与者。提出的研究应提供有关cAMP依赖性信号事件的新见解。阐明这些新相互作用的基础机制可能会为具有效应途径选择性的新特异性抑制剂的合理设计提供见解，这可能对chagas病的新疗法产生影响。