Physiological roles of schistosome TRP ion channels with atypical pharmacology

血吸虫 TRP 离子通道的生理作用与非典型药理学

• 批准号: 10078843
• 负责人: De'Broski R Herbert
• 金额: $ 40.25万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-17 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078843
• 关键词: Affect; Anthelmintics; Autophagocytosis; Behavior; Biochemistry; Biological; Biology; Bradykinin; Calcium; Capsaicin; Cations; Cessation of life; Childhood; Common Core; Development; Electrophysiology (science); Environment; Family; Female; Future; Genome; Helminths; Homeostasis; Human; Hyperactivity; Infection; Inflammatory; Inflammatory Response; Ion Channel; Ions; Knock-out; Life Cycle Stages; Mammals; Mediating; Membrane Proteins; Molecular; Molecular Genetics; Morbidity - disease rate; Morphology; Mus; Nutrient; Organism; Parasites; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacology; Physiological; Physiology; Platyhelminths; Play; Praziquantel; Property; Proteins; Publishing; RNA Interference; Regulation; Role; Schistosoma; Schistosoma mansoni; Schistosomiasis; Second Messenger Systems; Sensory; Signal Transduction; Site; Stimulus; Structure; System; TRP channel; TRPA channel; TRPV channel; TRPV1 gene; Testing; Therapeutic; Tissues; Tropical Disease; Vaccines; Vacuole; Variant; egg; experimental study; in vivo; insight; knock-down; male; member; migration; neglected tropical diseases; neuromuscular; new therapeutic target; nociceptive response; novel; protein complex; receptor; response; sensory stimulus; targeted treatment; therapeutic target; tool; trafficking

Parasitic flatworms of the genus Schistosoma cause schistosomiasis, a tropical disease affecting hundreds of millions of people worldwide. There is no vaccine, and only a single drug (praziquantel) available for treatment and control. Many anthelmintics, likely including praziquantel, act on ion channels, membrane protein complexes that are essential for normal functioning of the neuromusculature and other tissues. However, few helminth ion channel families have been assessed for their properties and for their roles in parasite physiology. One such overlooked group of helminth ion channels is the transient receptor potential (TRP) channel superfamily. Members of the TRP channel family are widely diverse in their activation mechanisms and ion selectivity, but share a common core structure. They are critical to transducing sensory signals, responding to a wide range of external stimuli, and are also involved in other functions, such as regulating intracellular calcium and organellar ion homeostasis and trafficking. TRP channels also respond to endogenous agents, including those involved in inflammatory signaling. Our published and preliminary pharmacological and knockdown studies show that schistosome TRP channels can be targeted to impact normal neuromuscular and sensory function. More significantly, they appear to have novel pharmacological sensitivities. Specifically, our results are consistent with the schistosome TRPA channel (SmTRPA) having at least some of the pharmacological sensitivities of mammalian TRPV1 channels, particularly notable as there are no TRPV channels represented in schistosome genomes. Preliminary functional expression studies support this contention. We hypothesize that in schistosomes, SmTRPA fulfills some of the roles of missing TRPV channels. We also hypothesize that SmTRPA and perhaps other schistosome TRP channels regulate critical parasite-host interactions required for successful infection. This project will use parallel strategies to define the roles SmTRPA and other TRP channels play in schistosome biology, including parasite-host interactions, and assess SmTRPA channel function directly. Finally, we hypothesize that the schistosome TRP channel, SmTRPML, plays key roles in schistosome endolysosomal physiology that can impact autophagy and nutrient acquisition. Our studies will elucidate the biological roles and physiological properties of an almost entirely unexplored family of parasite ion channels, information which could in the future be used to provide novel candidate targets for new or repurposed antischistosomal agents. The specific aims of this project are to: 1) Determine the role that SmTRPA and other TRP channels play in the schistosome life cycle, including in parasite-host interactions; 2) Use functional expression to test whether schistosome sensitivity to TRPV1 modulators is mediated specifically by SmTRPA; and 3) Elucidate the role of the schistosome TRPML channel in endolysosomal functions, including nutrient acquisition and autophagy.

血吸虫属的寄生扁形虫引起血吸虫病，一种热带疾病 影响着全球数亿人没有疫苗，只有一种药物（吡喹酮） 可用于治疗和控制。许多驱虫药，可能包括吡喹酮，作用于离子通道， 膜蛋白复合物是神经肌肉组织和其他组织的正常功能所必需的。 组织中然而，很少有蠕虫离子通道家族被评估其性质和作用 在寄生虫生理学中。其中一个被忽视的蠕虫离子通道是瞬时受体电位 (TRP)通道超家族TRP通道家族的成员在其激活方面是广泛多样的 机制和离子选择性，但共享一个共同的核心结构。它们对于传导感觉信号 信号，响应广泛的外部刺激，也参与其他功能，如 调节细胞内钙和细胞器离子稳态和运输。TRP渠道也响应 内源性因子，包括参与炎症信号传导的那些。我们已公布的和初步的 药理学和敲低研究表明，可靶向干扰TRP通道， 神经肌肉和感觉功能正常更重要的是，它们似乎具有新的药理学作用， 敏感性具体而言，我们的结果与具有在 哺乳动物TRPV 1通道的药理学敏感性的至少一些，特别值得注意的是， 没有TRPV通道出现在染色体组中。初步功能表达研究 支持这一论点。我们假设，在染色体中，SmTRPA履行了缺失的一些作用， TRPV频道我们还假设SmTRPA和其他可能的TRP通道调节 成功感染所需的关键寄生虫-宿主相互作用。该项目将使用并行策略， 定义SmTRPA和其他TRP通道在寄生生物学中的作用，包括寄生宿主 相互作用，并直接评估SmTRPA通道功能。最后，我们假设， SmTRPML通道在血吸虫内溶体生理学中发挥关键作用，可以影响自噬和 养分获取我们的研究将阐明一个几乎没有的生物学作用和生理特性。 完全未开发的寄生虫离子通道家族，未来可用于提供 新的或再利用的抗溶酶体剂的新的候选靶点。该项目的具体目标是： 1)确定SmTRPA和其他TRP通道在复杂的生命周期中发挥的作用，包括在 2）利用功能性表达来检测病原体对TRPV 1的敏感性 调节剂是由SmTRPA特异性介导的;和3）阐明线粒体TRPML通道的作用 内溶酶体功能，包括营养获取和自噬。

项目成果

Cellular context of IL-33 expression dictates impact on anti-helminth immunity.

• DOI: 10.1126/sciimmunol.abc6259
• 发表时间: 2020-11-13
• 期刊: Science immunology
• 影响因子: 24.8
• 作者: Hung LY;Tanaka Y;Herbine K;Pastore C;Singh B;Ferguson A;Vora N;Douglas B;Zullo K;Behrens EM;Li Hui Tan T;Kohanski MA;Bryce P;Lin C;Kambayashi T;Reed DR;Brown BL;Cohen NA;Herbert DR
• 通讯作者: Herbert DR

Schistosome TRPML channels play a role in neuromuscular activity and tegumental integrity.

血吸虫 TRPML 通道在神经肌肉活动和皮膜完整性中发挥作用。

• DOI: 10.1016/j.biochi.2021.12.018
• 发表时间: 2022-03
• 期刊: Biochimie
• 影响因子: 3.9
• 作者: Bais S;Norwillo A;Ruthel G;Herbert DR;Freedman BD;Greenberg RM
• 通讯作者: Greenberg RM

Parasitic helminth infections in humans modulate Trefoil Factor levels in a manner dependent on the species of parasite and age of the host.

• DOI: 10.1371/journal.pntd.0009550
• 发表时间: 2021-10
• 期刊: PLoS neglected tropical diseases
• 影响因子: 3.8
• 作者: Adewale B;Heintz JR;Pastore CF;Rossi HL;Hung LY;Rahman N;Bethony J;Diemert D;Babatunde JA;Herbert DR
• 通讯作者: Herbert DR

"MrgprA3 neurons selectively control myeloid-derived cytokines for IL-17 dependent cutaneous immunity".

“MrgprA3 神经元选择性控制骨髓源性细胞因子，实现 IL-17 依赖性皮肤免疫”。

• DOI: 10.21203/rs.3.rs-3644984/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Inclan-Rico,JuanM;Napuri,CamilaM;Lin,Cailu;Hung,Li-Yin;Ferguson,AnnabelA;Wu,Qinxue;Pastore,ChristopherF;Stephenson,Adriana;Femoe,UlrichM;Rossi,HeatherL;Reed,DanielleR;Luo,Wenqin;Abdus-Saboor,Ishmail;Herbert,De'BroskiR
• 通讯作者: Herbert,De'BroskiR

Neuroimmune regulatory networks of the airway mucosa in allergic inflammatory disease.

• DOI: 10.1002/jlb.3ru0121-023r
• 发表时间: 2022-01
• 期刊: Journal of leukocyte biology
• 影响因子: 5.5
• 作者: Jean EE;Good O;Rico JMI;Rossi HL;Herbert DR
• 通讯作者: Herbert DR