Polarity Establishment Mechanisms in Candida albicans

白念珠菌菌丝顶端极性建立和维持的分子机制 增长在很大程度上仍然是未知的，这种知识上的差距限制了模型的发展， 如何防止菌丝侵入组织。与这项研究计划相关的长期目标 是了解极性是如何建立在菌丝尖端（菌丝指导）和如何菌丝指导 蛋白质介导C.白色念珠菌接触感应（触变）和侵入行为。这些目标将 通过追求以下三个具体目标实现了该建议：1）鉴定重要的蛋白质 2）确定菌丝顶端极性建立的程度 蛋白质参与向触性和侵袭; 3）建立已知的 菌丝引导GTlp，Rsrlp，控制菌丝引导。在第一个目标下，一个向前的遗传筛选将 用于鉴定皮质定位的极性建立蛋白，（通过GFP融合体的定位）和 分析缺乏这些尖端定位的候选蛋白的菌株中的极性建立表型。下 第二个目标，菌丝导向蛋白介导菌丝重定向以响应脊的能力 并确定上皮细胞损伤。在第三个目标下，遗传和生物化学相互作用 Rsrlp与菌丝顶端的独特极性蛋白之间的关系将由a）顶端的定位确定 缺乏Rsrlp活性的菌株中的极性结构（极性体和Spitzenkorper），B）免疫共沉淀 Rsrlp和尖端极性蛋白之间的物理相互作用的分析，以及c）Rsrlp和尖端极性蛋白之间的上位性分析。 缺乏Rsrlp和第二极性建立蛋白的菌株的趋触性和侵袭能力。 这项拟议中的研究意义重大，因为它将提供了解菌丝如何 以定向方式生长，以及这与临床相关过程-宿主组织侵入如何相关。在 同时，对菌丝极性建立的基础性新认识也有期待 推进其他丝状真菌和其他极化真核生物中极性反应的一般领域 细胞系统这是C语言中一个重要而又未被充分研究的领域。白色念珠菌生物学适用于 了解系统性C.白色念珠菌感染 免疫功能低下的患者。

The molecular mechanism by which polarity is established and maintained during Candida albicans hyphal tip growth remains largely unknown and this gap in knowledge has limited the development of models for how hyphae invade tissues how this can be prevented. The long-term goal associated with this research program is to understand how polarity is established at hyphal tips (hyphal guidance) and how hyphal guidance proteins mediate C. albicans contact sensing (thigmotropic) and invasive behavior. These objectives will be achieved in this proposal by pursuing the following three Specific Aims: 1) Identify proteins that are important for polarity establishment at hyphal tips; 2) Determine the extent to which tip-localized polarity establishment proteins are involved in thigmotropism and invasion; and 3) Establish the mechanism by which the known hyphal guidance GTPase, Rsrlp, controls hyphal guidance. Under the first aim, a forward genetic screen will be used to identify cortically-localized polarity establishment proteins, (by localization of GFP fusions) and by analysis of polarity establishment phenotypes in strains lacking these tip-localized candidate proteins. Under the second aim, the ability of hyphal guidance proteins to mediate hyphal re-orientation in response to a ridge and epithelial cell damage will be determined. Under the third aim, genetic and biochemical interactions between Rsrlp and unique polarity proteins at the hyphal tip will be determined by a) localization of tip polarity structures (polarisome and Spitzenkorper) in strains lacking Rsrlp activity, b) co-immunoprecipitation analysis of physical interactions among Rsrlp and tip polarity proteins, and c) epistasis analysis of thigmotropic and invasive ability of strains lacking both Rsrlp and a second polarity establishment protein. The proposed research is significant because it will provide the knowledge needed to understand how hyphae grow in a directional manner and how this is related to a clinically relevant process - host tissue invasion. At the same time, the fundamental new knowledge obtained about polarity establishment in hyphae is expected to advance the general field of polarity responses in other filamentous fungi and in other polarized eukaryotic cell systems. This is an important and under-investigated area of C. albicans biology that has applicability to understanding the pathogenesis of tissue invasion during systemic C. albicans infections in immunocompromised patients.