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）：此福格蒂国际研究合作奖 (FIRCA) 申请基于母基金 R01 CA071649-11（首席研究员 Altschuler，Daniel），旨在扩大外国科学家（Martin Edreira 博士）和机构（布宜诺斯艾利斯大学，布宜诺斯艾利斯，阿根廷）的研究能力，利用 cAMP 信号通路寻找潜在靶标 全球公共卫生疾病，即恰加斯病。恰加斯病是一种由原生动物寄生虫克氏锥虫引起的危及生命的疾病。该病流行于南美洲贫困农村地区，估计感染人数达 1000 万，每年死亡人数高达 25,000 人，令人震惊，由于移民到发达国家，其影响正在蔓延至全球；据估计，目前约有 30 万受感染的移民居住在美国。目前还没有可用的疫苗，而 20 世纪 70 年代初推出的药物，即硝呋替莫和苯硝唑，是目前唯一可用的治疗选择。然而，这些抗寄生虫药物的功效有限且毒性高。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，cAMP 依赖性信号传导途径的作用已被充分确定为克氏锥虫细胞周期及其入侵宿主能力的调节剂。尽管人们的注意力集中在参与 cAMP 合成（即环化酶）和降解（即磷酸二酯酶）的推定机制上，但潜在的新 cAMP 效应途径的作用目前尚不清楚。父母资助的目标是鉴定和表征哺乳动物细胞中新的不依赖于 PKA 的 cAMP 效应通路，以及开发用于分析的特定试剂。本申请要测试的一般假设是，与哺乳动物细胞类似，多个 cAMP 效应器途径可能在这种人类寄生虫的致病机制中发挥重要作用。为了解决这个问题，提出了两个具体目标：Sp。目标 1：识别和表征 T. cruzi 和 Sp. 中新的 cAMP 效应子。目标 2：确定特定哺乳动物 cAMP 效应子在宿主入侵过程中的作用。成功完成所提出的目标有可能揭示 cAMP 生物学的新方面，并为查加斯病的发病机制提供新的见解。尽管大部分研究将由阿根廷布宜诺斯艾利斯大学的埃德雷拉博士进行，但匹兹堡大学家长资助产生或目前正在处理的所有工具都将随时可供埃德雷拉博士的研究使用。在cAMP生物学和恰加斯研究方面拥有丰富专业知识的实验室之间的密切合作应该提供一个富有成效的环境，这将有可能推动克氏锥虫生物学领域及其与宿主细胞的相互作用，并有望为未来的干预确定新的和独特的目标。 公共卫生相关性：恰加斯病是一种由原生动物寄生虫克氏锥虫引起的潜在危及生命的疾病。它是美洲的流行病，对拉丁美洲贫困农村人口的健康构成严重威胁。现有的抗寄生虫药物效果有限且毒性很大。因此，迫切需要新的治疗方法，这意味着识别新的潜在靶点并设计新的抗锥虫治疗药物。 cAMP 通路参与克氏锥虫的增殖、分化和侵袭，对于寄生虫至关重要，并且可能成为新药的靶标。该申请的总体目标侧重于表征克氏锥虫生物学和入侵期间宿主细胞中涉及的 cAMP 通路内的效应器相互作用，以便确定可用作药物设计目标的特定关键参与者。所提出的研究应该为 cAMP 依赖性信号传导事件提供新的见解。揭示这些新相互作用背后的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，这可能对恰加斯病新疗法的开发产生影响。