Mechanisms of synapse formation and axon termination in C. elegans

描述（由申请人提供）：突触是大脑中传递信息流的连接。一些导致突触或突触功能丧失的疾病和状况可以被认为是“突触疾病”，包括神经退行性疾病，如阿尔茨海默病，以及中风对中枢神经系统的创伤。虽然疾病特异性治疗将有所帮助，但广泛的基础治疗，如触发新突触形成或稳定现有突触的治疗，也将是非常有价值的，可能会减缓疾病进展，或改善创伤或疾病发作后的恢复。据我们所知，目前还没有一种药物能特别触发新的突触形成或稳定现有的连接。实现这一里程碑仍然是医学界的首要、紧迫和迫切的目标。实现这一目标的第一步是了解大自然如何构建突触，从而确定最佳的治疗靶点。我们研究计划的长期目标是识别和理解协调突触形成的分子参与者，并将突触形成与其他关键的神经发育过程（如轴突终止）结合起来。重要的是，突触的形成是一个进化上保守的过程，发生在简单的无脊椎动物中，如秀丽隐杆线虫，通过人类。因此，对突触形成至关重要的分子也将在进化上保守。以秀丽隐杆线虫为模型系统，我们的目标是快速有效地鉴定在突触形成和轴突终止中起作用的保守分子。虽然我们要完全理解突触是如何建立和维持的还有很长的路要走，但重要的是要强调，许多已知的调节这一过程的分子是用秀丽隐杆线虫鉴定出来的。其中一个调节突触形成、轴突终止、引导和再生的分子是突触前形态调节剂(RPM)-1。虽然它作为神经发育调节蛋白的关键和核心作用可能使RPM-1成为理想的治疗靶点，但我们对RPM-1如何发挥作用的了解仍然非常有限。为了深入了解RPM-1的作用机制，我们最近进行了蛋白质组学筛选，以确定与RPM-1结合的蛋白质。在这项提议中，我们的目标是研究我们在蛋白质组学筛选中鉴定的两个新的，保守的RPM-1结合蛋白NPP-17和T23F11.1。我们将在秀丽隐杆线虫中使用转基因、遗传学和细胞生物学来确定NPP-17和T23F11.1是否在突触形成和轴突终止中起作用。我们还将确定NPP-17和T23F11.1是否介导RPM-1的功能，以及NPP-17和T23F11.1如何与已知的RPM-1下游通路相关。重要的是，T23F11.1和NPP-17都是保守分子，在神经元中没有已知的功能。因此，了解这些分子的神经元功能和作用机制将使我们更接近了解如何建立突触的目标，以及从药理学上操纵这一过程以获得最大治疗效果的最终目标。

DESCRIPTION (provided by applicant): Synapses are the connections that transmit information flow in the brain. Several diseases and conditions that result in a loss of synapses or synaptic function can be thought of as "diseases of the synapse" including neurodegenerative diseases, such as Alzheimer's disease, and trauma to the central nervous system from stroke. While disease-specific therapies will be helpful, broad based therapies such as those that trigger new synapse formation or stabilize existing synapses will also be extremely valuable potentially slowing disease progression, or improving recovery following trauma or disease onset. To our knowledge there is no pharmaceutical that specifically triggers new synapse formation or stabilizes existing connections. Achieving this milestone remains a primary, pressing and urgent goal of the medical community. The first step in achieving this goal is to understand how nature builds a synapse, allowing the identification of the best therapeutic targets. The long-term goal of our research program is to identify and understand the molecular players that orchestrate synapse formation, and integrate synapse formation with other key neurodevelopmental processes, such as axon termination. Importantly, synapse formation is an evolutionarily conserved process that occurs in simple invertebrates, such as the worm C. elegans, through human beings. Thus, molecules that are critical to synapse formation will also be evolutionarily conserved. Using C. elegans as a model system, we aim to rapidly and efficiently identify conserved molecules that function in synapse formation and axon termination. While we are a long way from fully understanding how a synapse is built and maintained, it is important to emphasize that many of the molecules that are known to regulate this process were identified using C. elegans. One such molecule that regulates synapse formation, as well as axon termination, guidance and regeneration is the Regulator of Presynaptic Morphology (RPM)-1. While its key and central role as a neurodevelopmental regulatory protein potentially makes RPM-1 an ideal therapeutic target, we still have very limited knowledge on how RPM-1 functions. To gain insight into RPM-1's mechanism of action, we have recently performed a proteomic screen to identify proteins that bind to RPM-1. In this proposal, we aim to study two novel, conserved RPM-1 binding proteins that we identified in our proteomic screen, NPP-17 and T23F11.1. We will use transgenics, genetics and cell biology in C. elegans to determine if NPP-17 and T23F11.1 function in synapse formation and axon termination. We will also determine if NPP-17 and T23F11.1 mediate RPM-1 function, and how NPP-17 and T23F11.1 relate to pathways that are known to act downstream of RPM-1. Importantly, both T23F11.1 and NPP-17 are conserved molecules with no known function in neurons. Thus, understanding the neuronal function and mechanisms of action for these molecules will bring us significantly closer to the goal of understanding how to build a synapse, and the ultimate goal of pharmacologically manipulating this process for maximum therapeutic impact.