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（申请人提供）：Fogarty国际研究合作奖（FIRCA）申请，基于父母资助R 01 CA 071649 -11（首席研究员Altschuler，丹尼尔）旨在扩大外国科学家的研究能力（马丁·埃德雷拉博士）和机构（Universidad de Buenos Aires，Buenos Aires，Argentina），利用cAMP信号传导途径寻找全球公共卫生疾病即恰加斯病的潜在靶标。查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。流行于南美洲的贫困农村地区，感染人口估计为1000万，每年死亡人数达到惊人的25，000人，由于移民到发达国家，其影响正在成为全球性的;估计表明，目前约有30万受感染的移民居住在美国。没有可用的疫苗，1970年代初引入的药物，即硝呋替莫和苄硝哒唑，是目前唯一可用的治疗选择。然而，这些抗寄生虫药物显示出有限的功效和高毒性。因此，迫切需要开发新的替代治疗方法。在寄生虫和宿主哺乳动物细胞中，cAMP依赖性信号通路的作用被很好地确定为T. cruzi氏细胞周期及其入侵宿主的能力。虽然很多注意力集中在cAMP的合成（即环化酶）和降解（即磷酸二酯酶）中涉及的假定机制上，但潜在的新cAMP效应途径的作用目前尚不清楚。亲本资助的目标是鉴定和表征哺乳动物细胞中新的PKA非依赖性cAMP效应子途径，以及开发用于其分析的特异性试剂。在本申请中待测试的一般假设是，与哺乳动物细胞类似，多种cAMP效应子途径可能在该人类寄生虫使用的致病机制中起重要作用。提出了两个具体的目标，以接近这一点：SP。目的1：确定和表征新的cAMP效应在T。目的2：确定特定哺乳动物cAMP效应子在宿主入侵过程中的作用。成功完成拟议的目标有可能揭示cAMP生物学的新方面，并提供新的见解，在南美锥虫病的发病机制。虽然大多数研究将由阿根廷布宜诺斯艾利斯大学的Edreira博士进行，但匹兹堡大学的母基金产生或目前正在进行的所有工具都将随时可供Edreira博士的研究使用。在cAMP生物学和恰加斯病研究方面具有强大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T。Cruzi生物学，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。它是美洲的地方病，对生活在拉丁美洲贫困农村人口中的人的健康构成严重威胁。现有的抗寄生虫药物效果有限，而且毒性很高。因此，迫切需要新的治疗方法，这意味着识别新的潜在靶标和设计用于抗锥虫治疗的新药。cAMP途径参与T.克氏增殖、分化和侵袭是寄生虫所必需的，并且可以成为新药的靶点。该申请的总体目标集中于在侵袭期间涉及克氏锥虫生物学和宿主细胞中的cAMP途径内的效应物相互作用的表征，以便鉴定用作药物设计靶标的特定关键参与者。提出的研究应该提供新的见解cAMP依赖性信号事件。揭示这些新的相互作用的机制可能会提供新的特异性抑制剂的合理设计与效应途径的选择性，可能有影响的新疗法的发展恰加斯病的见解。