Molecular & cellular basis for host-pathogen interactions

超出空间 但前提是。 烟曲霉(Aspergillusfumigatus，Af)是导致侵袭性曲霉病(IA)的主要原因。 免疫功能受损的个体数量不断增加。伊曲康唑和两性霉素B是唯一的 目前可用的治疗方法用于侵袭性菌丝生长逃逸宿主的先天 免疫系统。然而，它们在体内的有效性较低，对IA患者的预后也很差。 寻找(At)毒力因子是有问题的，因为明显候选基因的突变确实存在。 而不是降低毒力。有趣的是，大多数影响病程的基因减缓了菌丝生长的速度。 延期，也许会让主机有更多的时间进行防御。AF以菌丝体的形式生长 通过培养基极化菌丝生长。这种增长模式要求新材料不断地 移到菌丝生长的顶端。我们的实验室一直致力于阐明多巴的功能， 从真菌到哺乳动物进化保守的蛋白质家族的创始成员。早期工作 来自我们实验室的研究表明，多巴是一种参与蛋白质运输的必要基因。具体目标1 将检验这样一个假设，即建立和维持高度极化的菌丝生长的能力是 免疫低下患者避免先天免疫的机制，是一个主要贡献 丝状真菌病原体的毒力因子。影响真菌生长的突变将在 动物细胞系。多巴突变体的毒力将在小鼠侵袭性肺组织中进行评估 曲霉病模型。特殊目标2将检验Af多巴(多巴)和多巴蛋白的假设 代表了极化细胞生长所需的细胞蛋白运输的一个新的和必要的组成部分 对环境信号的反应。多巴蛋白将通过GFP融合在活细胞中定位。这个 多巴在其他已知的极性决定因素的定位中的作用将被研究。多巴相互作用 蛋白质将通过多种方法鉴定，以阐明极地生长的机制。这 该方法将有助于理解将信号与菌丝联系起来的分子机制 成长。具体目标3将检验Af有一个隐秘的性周期的假设，该周期可以被操纵来 发展减数分裂遗传学作为Af.性遗传学的增加对研究人员来说将是无价的 烟曲霉的研究。

EXCEED THE SPACE PROVIDED. Aspergillus fumigatus (Af) is the major cause of invasive aspergillosis (IA), an often-fatal disease in the growing population of immunocompromised individuals. Itraconazole and amphotericin B are the only currently available treatments for those cases where invasive hyphal growth escapes the host's innate immune system. However, their effectiveness in vivo is low and the prognosis for individuals with IA is poor. The search for (At) virulence factors has been problematic because mutations in the obvious candidates do not reduce virulence. Interestingly, the majority of genes that affect pathogenesis slow the rate of hyphal extension, perhaps giving the host more time to mount a defense. Af grows as a mycelium that extends through medium via polarized hyphal growth. This mode of growth requires that new materials be constantly moved to the growing tip of the hypha. Our laboratory has been involved in elucidating the function of DopA, the founding member of a protein family that is evolutionary conserved fromfungi to mammals. Earlier work from our lab indicates that DopA is an essential gene that is involved in protein trafficking. Specific Aim 1 will test the hypothesis that the ability to establish and maintain highly polarized hyphal growth is a key mechanism for avoidance of innate immunity in immunocompromised patients, and is a major contributing factor in virulence of filamentous fungal pathogens. Mutations that affect fungal growth will be studied in animal cell lines. The virulence of dopA mutants will be assessed in the mouse invasive pulmonary aspergillosis model. Specific Aim 2 will test the hypothesis that Af DopA (DopeyA) and An DopA proteins represent a novel and essential component of cellular protein trafficking required for polarized cell growth in response to environmental signaling. DopA protein will be localized in living cells by using GFP fusions. The role of DopA in the localization of other known polarity determinants will be investigated. DopA interacting proteins will be identified by a number of methods to elucidate the mechanisms of polar growth. This approach will contribute to an understanding of the molecular mechanisms that link signaling to hyphal growth. Specific Aim 3 will test the hypothesis that Af has a cryptic sexual cycle that can be manipulated to develop meiotic genetics as a tool for Af. The addition of sexual genetics will be invaluable to investigators studying Aspergillus fumigatus.