Exploiting the cAMP pathway in Chagas Disease Therapy

描述(由申请人提供)：Fogarty国际研究合作奖(FIRCA)的申请基于父母的资助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，阿根廷布宜诺斯艾利斯)的研究能力，利用cAMP信号通路寻找一种全球公共卫生疾病的潜在靶点，即查加斯病。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。它是南美洲贫穷农村地区的地方病，估计感染人口为1000万，每年令人震惊的死亡人数为2.5万人，由于移民到发达国家，其影响正在变得全球性；估计表明，目前约有30万受感染的移民生活在美国。目前还没有疫苗，20世纪70年代初S引入的药物，即硝呋莫司和苯硝唑是目前唯一可用的治疗方案。然而，这些抗寄生虫药物显示出有限的疗效和高毒性。因此，迫切需要开发新的替代治疗方法。CAMP依赖的信号通路在寄生虫和宿主哺乳动物细胞中的作用是公认的，它是克氏锥虫细胞周期及其入侵宿主能力的调节器。虽然cAMP合成(即环化酶)和降解(即磷酸二酯酶)的可能机制引起了人们的极大关注，但潜在的新cAMP效应通路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非PKA依赖的cAMP效应通路，以及开发用于分析它们的特定试剂。在这一应用中需要检验的一般假设是，类似于哺乳动物细胞，多个cAMP效应通路可能在这种人类寄生虫的致病机制中发挥重要作用。为了实现这一目标，提出了两个具体目标：SP。目的1：鉴定和鉴定克氏锥虫和沙门氏菌中新的cAMP效应因子。目的2：研究哺乳动物特异性cAMP效应分子在宿主入侵中的作用。成功完成拟议的目标有可能发现cAMP生物学的新方面，并为恰加斯病的发病机制提供新的见解。虽然大多数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，但匹兹堡大学父母拨款产生的或目前正在进行的所有工具都将随时可用于埃德雷拉博士的研究。在营地生物学方面拥有强大专业知识的实验室和恰加斯研究机构之间的密切合作应该会提供一个富有成效的环境，潜在地促进克氏锥虫生物学领域及其与宿主细胞的相互作用，并有望确定未来干预的新的和独特的靶标/S。

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.