Horseman, pass by: finding post-developmental functions of essential genes

描述(申请人提供)：活的生物体是高效的，经常为了不同的目的多次重复使用相同的基因。如果一个基因的一个功能是必不可少的，那么突变的死亡或停滞就会掩盖后来的其他功能。这种对必需基因后期功能的盲点在神经系统中尤其麻烦。大多数神经元不能从干细胞群中再生，因此必须在有机体的整个生命过程中存活并保持其信息处理能力。为了完成这一生存壮举，神经元必须保持其结构，并在受损时进行修复。但由于维持和再生发生在发育后，基本基因对维持和再生老化神经元的作用还知之甚少。该项目开发了一种在线虫中实现基因失活的空间和时间控制的新策略。通过使用这一策略，有可能绕过对必需基因的最初要求。此外，与现有的有条件或可诱导的基因敲除技术相比，该策略有一个关键的优势：它与遗传筛选相兼容。因此，这一策略打破了阻止基因筛查发现必要基因后期功能的障碍。这一重要进展将使必要基因的多种功能无论出现在哪里，都可以被梳理出来。该项目利用这一策略来发现神经元中特定的必需基因的功能，重点是细胞的生存、发育、轴突和突触的维持以及再生。这些实验应该确定一组共同的因素，这些因素有助于在发育结束很长一段时间后，保护和恢复所有神经系统的神经功能。许多神经系统疾病的一个特点是起病延迟。此外，即使在没有已知疾病的情况下，也会发生与年龄相关的神经系统功能下降。这些观察表明，成熟神经系统发育后的变化会导致疾病易感性和功能丧失。通过在神经元发育完成后使基因失活，该项目将确定老化神经元中保守基因的关键功能，与衰老、疾病易感性和药物靶标发现具有广泛的相关性。 与公共健康相关：随着神经元的老化，它们需要保持其功能和结构，并在受损时进行自我修复。该项目将开发一种新的基因失活时空调控技术。通过在神经元发育完成后使基因失活，该项目将确定老化神经元中保守基因的关键功能，与衰老、疾病易感性和药物靶标发现具有广泛的相关性。

DESCRIPTION (provided by applicant): Living organisms are highly efficient and often reuse the same genes multiple times for different purposes. If one function of a gene is essential, death or arrest of the mutant masks other, later functions. This blind spot to later functions of essential genes is particularly troublesome in the nervous system. Most neurons can't be renewed from stem cell populations and therefore must survive and preserve their information- processing capabilities throughout the life of the organism. To accomplish this feat of survival, neurons must maintain their structure and repair it when damaged. But because maintenance and regeneration occur after development, the contribution of essential genes to maintaining and regenerating aging neurons is poorly understood. This project develops a novel strategy in C. elegans for achieving spatial and temporal control of gene inactivation. By using this strategy, it is possible to circumvent the initial requirement for essential genes. Further, the strategy has a critical advantage over existing techniques for making conditional or inducible knockouts: it is compatible with genetic screens. Thus, this strategy breaks down the barrier that prevents genetic screens from finding the later functions of essential genes. This important advance will enable multiple functions of essential genes to be teased apart wherever they occur. This project deploys this strategy to discover the function of essential genes specifically in neurons, focusing on cell survival, development, maintenance of axons and synapses, and regeneration. These experiments should identify a set of common factors that help preserve and restore neural function in all nervous systems, long after development has ended. A hallmark of many neurological diseases is delayed onset. Further, age-related decline in nervous system function occurs even in the absence of known disease. These observations suggest that post-developmental changes in the mature nervous system result in disease susceptibility and loss of function. By inactivating genes in neurons after their development is complete, this project will identify critical functions for conserved genes in aging neurons, with broad relevance for aging, disease susceptibility, and drug target discovery. PUBLIC HEALTH RELEVANCE: As neurons age, they need to maintain their function and structure, and repair themselves when damaged. This project will develop a novel genetic technology for the spatial and temporal regulation of gene inactivation. By inactivating genes in neurons after their development is complete, this project will identify critical functions for conserved genes in aging neurons, with broad relevance for aging, disease susceptibility, and drug target discovery.