Genetic and neural basis of pheromone sensory integration in nematodes

描述（由申请人提供）：感官缺陷是一个主要的人类健康问题。虽然缺陷通常发生在感觉检测的水平上，但这些过程也可能在感觉整合的水平上失败。因此，在检测和整合的水平上理解感觉信号是至关重要的。化学信号，如小分子信息素和利它素，被人类和大多数其他动物用来与他们的环境交流和反应。这些化学物质可以引起非常不同的反应，这取决于外部（环境影响）或接受者的内部状态。虽然这种反应的灵活性是至关重要的动物生存，神经机制，有助于这种adaptability没有很好地理解。为了理解这一过程，必须确定多个刺激的信号整合的位点，并随后确定这些信号如何收敛以促进新的反应。由于其实验上的易变性，这些机制可以在线虫C. elegans，它在感觉神经元中使用保守的化学信号转导复合物。对C.线虫不仅将改善化学感受性疾病的诊断和治疗方法，而且还将导致通过干扰信息素信号来控制寄生线虫的新策略。为了确定感觉信号整合的机制，该建议侧重于两个保守的蛔虫（ascr）信息素，ascr#3和ascr#9，产生性二态性（内在）和上下文特定（环境）的行为反应。目的1：确定成年动物中ascr#3依赖的性二态信号的遗传、分子和神经基础。对ascr#3的性二态行为反应需要来自ADL化学感觉神经元的感觉输入，这是通过很大程度上未定义的分子机制实现的。初步数据表明，这些性二态行为可能是由于神经元性别的差异，以及G蛋白偶联受体的SRBC家族的成员可能编码ascr#3特异性受体在ADL。该提案将确定和表征第一个成人特异性化学受体和调节ascr#3依赖性C的信号分子。elegans成年的行为和决定的基础上的性二型反应ascr#3。目的2：确定ascr#9在与其他信息素线索相结合的幼仔幼虫回避行为中的作用。在有限的资源下，许多线虫进入另一个发育阶段，称为dauer幼虫，这有助于传播（自由生活 线虫）和感染（寄生线虫）。保守的信息素ascr#9指导回避行为的dauer幼虫的几个物种时，与其他ascr线索组合，提供了一个很好的模型组合的感觉输入。该建议将具体确定ascr#9对幼虫回避的组合效应的神经基础，并通过分析野生C. elegans菌株。

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.