Hypoxia Adapatation and Fungal Virulence of Aspergillus fumigatus

描述（由申请人提供）：侵袭性曲霉病（IA）是由霉菌烟曲霉引起的，是一种研究不足的疾病，其重要性日益增加，每年在美国造成3,500多人死亡。对A.随着新医疗技术的发展，烟曲霉感染也急剧增加。目前，我们对这种常见霉菌引起疾病的机制的理解是有限的。虽然A.尽管烟曲霉在IA期间遇到显著的环境压力，但真菌如何适应在感染部位的体内发现的微环境尚未完全了解。我们发现A.烟曲霉在感染过程中遇到显著的缺氧。重要的是，我们已经发现，适应缺氧是遗传调节，在这种模具和真菌毒力所需的。因此，该提案的长期目标是确定该真菌用于适应缺氧并在免疫功能低下患者中引起疾病的分子机制。这可能会导致开发新的IA治疗干预措施。该建议有三个具体的目的，旨在确定缺氧适应的分子机制，介导的甾醇调节元件结合蛋白（SREBP），SrbA，介导缺氧适应和真菌毒力在A。烟熏。在目标1中，我们将定义SrbA在A中何时何地被激活。建立了SrbA介导的A. fumigatus缺氧适应模型的第一部分。烟熏。在目标2中，我们将识别和表征与SrbA相互作用的关键参与者，并可能调节其活性，将第二个调节层添加到我们的模型中。在目的3中，SrbA的关键下游效应物介导A.将对烟曲霉进行鉴定和表征。这三个目标的实现将为深入了解A.并首次为致病性霉菌中SREBP信号转导模型奠定了基础。这些特定目标的调查也将为未来的研究提供额外的目标，以阐明可能适用于广谱致病性霉菌的缺氧适应机制。公共卫生相关性：随着医疗技术的进步，普通霉菌引起的致命感染越来越普遍。这些感染的治疗选择非常有限，迫切需要新的治疗干预措施。该提案旨在发现新的治疗选择，以治疗由丝状霉菌烟曲霉引起的侵袭性曲霉病。

DESCRIPTION (provided by applicant): Invasive aspergillosis (IA) is caused by the mould Aspergillus fumigatus and is an understudied disease of growing significance that causes over 3,500 deaths in the United States annually. The spectrum of patients susceptible to A. fumigatus infections is also dramatically increasing with the development of new medical technologies. Currently, our understanding of the mechanisms utilized by this common mould to cause disease is limited. Though it is likely that A. fumigatus encounters significant environmental stress during IA, how the fungus adapts to micro-environments found in vivo at sites of infection is not fully understood. We have discovered that A. fumigatus encounters significant hypoxia during infection. Importantly, we have discovered that adaptation to hypoxia is genetically regulated in this mould and required for fungal virulence. Thus, the long-term objective of this proposal is to define the molecular mechanisms utilized by this fungus to adapt to hypoxia and cause disease in immunocompromised patients. This may lead to development of novel therapeutic interventions for IA. This proposal has three specific aims designed to define the molecular mechanism of hypoxia adaptation as mediated by a sterol-regulatory element binding protein (SREBP), SrbA, that mediates hypoxia adaptation and fungal virulence in A. fumigatus. In aim 1, we will define where and when SrbA is activated in A. fumigatus establishing the first part of a model of SrbA mediated hypoxia adaptation in A. fumigatus. In aim 2, we will identify and characterize the key players that interact with SrbA and likely regulate its activity adding the second regulatory layer to our model. In aim 3, the key downstream effectors of SrbA that mediate adaptation to hypoxia by A. fumigatus will be identified and characterized. Completion of these 3 aims will offer much needed insights into the mechanisms of a novel virulence attribute of A. fumigatus and lay the foundation for a model of SREBP signaling in a pathogenic mould for the first time. Investigations in these specific aims will also provide additional targets for future studies to elucidate mechanisms of hypoxia adaptation that may be applicable to a broad-spectrum of pathogenic moulds. PUBLIC HEALTH RELEVANCE: Lethal infections by common moulds are becoming increasingly common with advances in medical technologies. Treatment options for these infections are very limited, and new therapeutic interventions are urgently needed. This proposal seeks to discover new therapeutic options to treat invasive aspergillosis caused by the filamentous mould Aspergillus fumigatus.