Genetic and neural basis of pheromone sensory integration in nematodes

描述(申请人提供)：感官缺陷是一个主要的人类健康问题。虽然缺陷经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BOT检测和整合的水平上理解BOT的感觉信号是至关重要的。化学信号，如小分子信息素和凯洛酮，被人类和大多数其他动物用来与环境交流和做出反应。根据接受者的外部(环境影响)或内部状态，这些化学物质可以引起非常不同的反应。尽管这种反应灵活性对动物的生存至关重要，但促进这种适应性的神经机制还没有被很好地理解。为了理解这一过程，我们必须确定多个刺激信号整合的地点(S)，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中发现，线虫在感觉神经元中使用保守的化学信号转导复合体。识别线虫体内信号整合的机制不仅将改进化学感觉障碍的诊断和治疗方法，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，这个建议集中在两个保守的蛔虫苷(ASCR)信息素，ASCR#3和ASCR#9，它们产生性别二态(内在的)和上下文特定的(环境)行为反应。目的1：确定成年动物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ADL化学感觉神经元通过很大程度上未知的分子机制进行感觉输入。初步数据表明，这些性二型性行为可能是由于神经元性别的差异，SRBC家族G蛋白偶联受体的一个成员可能编码ADL中的ASCR#3特异性受体。本研究将鉴定和鉴定第一个成虫特异性化学受体(S)和信号分子，它们调节依赖于ASCR#3的线虫成虫行为，并确定对ASCR#3性二态反应的基础。目标2：结合其他信息素线索，确定ASCR#9在达尔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展阶段，称为达尔幼虫，这有利于扩散(在自由生活中 线虫)和感染(寄生线虫)。保守的信息素ASCR#9与其他ASCR信号一起出现时，可以指导几个物种的达尔幼虫的回避行为，为组合感觉输入提供了一个很好的模型。本研究将通过对线虫野生株的自然变异的分析，明确ASCR#9对幼虫回避的组合效应的神经基础，并确定ASCR#9依赖信号的分子机制。

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.