Genetic and neural basis of pheromone sensory integration in nematodes

线虫信息素感觉统合的遗传和神经基础

• 批准号: 8649158
• 负责人: Michael Patrick ODonnell
• 金额: $ 4.92万
• 依托单位: BRANDEIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649158
• 关键词: Address; Adult; Affect; Afferent Neurons; Animal Model; Animals; Behavior; Behavioral; CD2 gene; Caenorhabditis elegans; Chemicals; Chemoreceptors; Communication; Complex; Cues; Data; Defect; Detection; Development; Diagnosis; Disease; Environment; Family; G-Protein-Coupled Receptors; Genetic; Health; Human; Individual; Kairomones; Larva; Lead; Life; Methods; Modeling; Molecular; Molecular Genetics; Nematoda; Nematode infections; Neural Pathways; Neurons; Organism; Outcome; Parasitic infection; Parasitic nematode; Pheromone; Population; Process; Resources; Role; Sensory; Signal Transduction; Signaling Molecule; Site; Staging; Stimulus; Variant; Work; avoidance behavior; base; combat; combinatorial; experience; flexibility; improved; insight; male; mature animal; member; neuromechanism; novel; public health relevance; receptor; relating to nervous system; research study; response; sensory integration; sensory mechanism; sex; sexual dimorphism; small molecule

DESCRIPTION (provided by applicant): Sensory defects are a major human health concern. While defects can often occur at the level of sensory detection, these processes can also fail at the level of sensory integration. Therefore, it is essential to understand sensory signaling at bot the level of detection and integration. Chemical signals, such as small molecule pheromones and kairomones, are used by humans and most other animals to communicate with and respond to their environment. These chemicals can elicit very different responses depending on the external (environmental influences) or internal state of the recipient. Although this response flexibility is critical for animal survival, the neural mechanisms that contribute to this adaptabiity are not well understood. To understand this process, one must identify the site(s) of signal integration of multiple stimuli and subsequently determine how these signals converge to promote novel responses. Due to its experimental amenability, these mechanisms can be identified in the nematode, C. elegans, which uses conserved chemical signal transduction complexes in sensory neurons. Identification of the mechanisms of signal integration in C. elegans will not only improve methods for the diagnosis and treatment of chemosensory disorders, but will also lead to new strategies to control parasitic nematodes through interference with pheromone signaling. To identify mechanisms of sensory signal integration, this proposal focuses on two conserved ascaroside (ascr) pheromones, ascr#3 and ascr#9, which produce sexually-dimorphic (intrinsic) and context-specific (environmental) behavioral responses. Aim 1: Determine the genetic, molecular and neural basis of ascr#3-dependent sexually-dimorphic signaling in adult animals. Sexually dimorphic behavioral responses to ascr#3 require sensory input from the ADL chemosensory neurons via largely undefined molecular mechanisms. Preliminary data indicate that these sexually dimorphic behaviors may be due to differences in neuronal sex, and that a member of the SRBC family of G-protein coupled receptors may encode ascr#3-specific receptors in ADL. This proposal will identify and characterize the first adult-specific chemoreceptor(s) and signaling molecules that regulate ascr#3-dependent C. elegans adult behaviors and determine the basis of sexually dimorphic responses to ascr#3. Aim 2: Identify the role of ascr#9 in dauer larval avoidance behavior in combination with other pheromone cues. Under limited resources, many nematodes enter an alternative developmental stage, termed the dauer larva, that facilitates dispersal (in free living nematodes) and infection (in parasitic nematodes). The conserved pheromone ascr#9 directs avoidance behavior in dauer larvae of several species when presented in combination with other ascr cues, providing an excellent model for combinatorial sensory input. This proposal will specifically determine the neural basis of combinatorial effects of ascr#9 on larval avoidance and identify molecular mechanisms of ascr#9-dependent signaling through the analysis of natural variation in wild C. elegans strains.

描述（由申请人提供）：感觉缺陷是人类健康的一个主要问题。虽然缺陷经常发生在感官检测层面，但这些过程也可能在感官整合层面失败。因此，了解机器人检测和集成层面的感觉信号至关重要。人类和大多数其他动物利用化学信号（例如小分子信息素和利他素）与环境进行交流并对其做出反应。这些化学物质可以根据接受者的外部（环境影响）或内部状态引起非常不同的反应。尽管这种反应灵活性对于动物的生存至关重要，但促成这种适应性的神经机制尚不清楚。为了理解这一过程，我们必须确定多种刺激的信号整合位点，并随后确定这些信号如何汇聚以促进新的反应。由于其实验适应性，这些机制可以在线虫（秀丽隐杆线虫）中发现，线虫使用感觉神经元中保守的化学信号转导复合物。鉴定线虫信号整合机制不仅将改进化学感应疾病的诊断和治疗方法，还将产生通过干扰信息素信号传导来控制寄生线虫的新策略。为了确定感觉信号整合的机制，该提案重点关注两种保守的蛔苷 (ascr) 信息素，ascr#3 和 ascr#9，它们产生性别二态性（内在）和上下文特定（环境）行为反应。目标 1：确定成年动物中 ascr#3 依赖的性二态性信号传导的遗传、分子和神经基础。对 ascr#3 的性别二态性行为反应需要 ADL 化学感觉神经元通过很大程度上未定义的分子机制进行感觉输入。初步数据表明，这些性别二态性行为可能是由于神经元性别差异所致，并且 G 蛋白偶联受体 SRBC 家族的成员可能编码 ADL 中的 ascr#3 特异性受体。该提案将鉴定和表征第一个成虫特异性化学感受器和信号分子，调节依赖于 ascr#3 的线虫成虫行为，并确定对 ascr#3 的性二态性反应的基础。目标 2：结合其他信息素线索，确定 ascr#9 在 dauer 幼虫回避行为中的作用。在资源有限的情况下，许多线虫进入另一个发育阶段，称为多尔幼虫，这有利于传播（在自由生活中） 线虫）和感染（寄生线虫）。当与其他 ascr 线索结合出现时，保守的信息素 ascr#9 可以指导多个物种的 dauer 幼虫的回避行为，为组合感觉输入提供了一个极好的模型。该提案将具体确定 ascr#9 对幼虫回避的组合效应的神经基础，并通过分析野生线虫菌株的自然变异来确定 ascr#9 依赖性信号传导的分子机制。