Hypha-to-yeast morphogenetic step in C. albicans

描述（由申请方提供）：白色念珠菌是最常见的人类侵袭性真菌病原体。念珠菌属是美国住院成人血液感染的第四大常见原因，也是儿童此类感染的第三大常见原因。38 - 49%的成年人和19.6%的儿童感染这种病毒死亡。念珠菌的形态发生开关从椭圆形酵母形式的丝状菌丝形式的增长是一个深入的研究课题。相反的形态发生步骤，从菌丝到酵母的生长形式，却很少受到关注。无论是在体外还是在人体组织中，这种真菌都不断地从菌丝形态转变为酵母形态生长。五C已经在动物研究中测试了从病原体到酵母形态发生步骤所需的白色念珠菌基因。所有这些都是念珠菌毒力所必需的。此外，在宿主中仅作为酵母生长的其它真菌物种比C.白色念珠菌，而在宿主组织中仅作为菌丝生长的物种毒性较低。 在这里，首次系统调查的菌丝到酵母形态发生步骤的C。白色的建议。将使用正向遗传方法，通过对C中这一发育步骤所需的分子进行全基因组筛选。白色念珠菌这一筛选将用两种新的遗传工具完成，这两种工具在初步实验中适用于C。白色念珠菌，显性选择标记和最大随机转座子系统。在使用这些工具的试点实验中，已经分离出了在菌丝到酵母开关中受损的突变体，并且已经鉴定出了这些突变体中被转座子破坏的遗传元件。除了筛选用我们的新工具创建的突变体集合之外，还提出利用可用的纯合和杂合突变体集合。 念珠菌形态发生的研究主要依赖于对相关酿酒酵母基因同源物的研究。然而，C. albicans和S.它们各自的环境所制造的酿酒酵母是非常不同的。已发现保守的调节模块控制两种生物体之间的不同输出。利用正向遗传学方法，研究了C.预计将鉴定出白色念珠菌。本研究为深入研究C.白色念珠菌人们希望，更好地了解这一关键因素的毒力将导致新的战略，治疗干预。

DESCRIPTION (provided by applicant): Candida albicans is the most frequently isolated invasive fungal pathogen of humans. Candida species are the fourth most common cause of bloodstream infections in hospitalized adults, and the third most common cause of such infections in children in the United States. 38 - 49% of adults, and 19.6% of children with such an infection die. Candida's morphogenetic switch from the oval yeast form to the filamentous hyphal form of growth is a subject of intense investigation. The opposite morphogenetic step, from the hyphal to the yeast form of growth, has received surprisingly little attention. Both in vitro and in human tissue the fungus constantly switches from hyphal to yeast-form growth. Five C. albicans genes required for the filament-to-yeast morphogenetic step have been tested in animal studies. All are required for Candida's virulence. Moreover, other fungal species which grow exclusively as yeast in the host are more virulent than C. albicans, while species which grow exclusively as hyphae in host tissue are less virulent. Here, the first systematic investigation of the hypha-to-yeast morphogenetic step of C. albicans is proposed. A forward genetic approach will be used, by performing a genome-wide screen for molecules that are required for this developmental step in C. albicans. This screen will be accomplished with two novel genetic tools adapted in preliminary experiments for use in C. albicans, a dominant selectable marker and a maximally random transposon system. In pilot experiments using these tools, mutants impaired in the hypha-to-yeast switch have already been isolated, and genetic elements disrupted by the transposon in these mutants have been identified. In addition to screening a mutant collection created with our novel tools, it is proposed to utilize available homozygous and heterozygous mutant collections. Studies of Candida morphogenesis have principally relied on investigation of homologs of relevant Saccharomyces cerevisiae genes. However, the demands on C. albicans and S. cerevisiae made by their respective environments are very different. Conserved regulatory modules have been found to control divergent outputs between the two organisms. With the forward genetic approach proposed here, previously unknown regulatory circuits in C. albicans are expected to be identified. This work will lay the foundation for in-depth studies of the mechanisms of hypha-to-yeast morphogenesis in C. albicans. It is hoped that a better understanding of this critical element of virulence will lead to new strategies for therapeutic intervention.