Hypoxia Adapatation and Fungal Virulence of Aspergillus fumigatus

描述(申请人提供)：侵袭性曲霉病(IA)是由霉菌烟曲霉菌引起的，是一种日益严重的未被研究的疾病，每年在美国导致超过3500人死亡。随着新医疗技术的发展，易受烟曲霉感染的患者范围也在急剧增加。目前，我们对这种常见霉菌致病机制的了解有限。虽然烟曲霉菌很可能在IA期间遇到了显著的环境压力，但这种真菌如何适应体内感染部位的微环境尚不完全清楚。我们发现，烟曲霉菌在感染过程中会遭遇严重的缺氧。重要的是，我们已经发现，对低氧的适应在这种模式中是基因调控的，是真菌毒力所必需的。因此，这项建议的长期目标是确定这种真菌用来适应低氧和导致免疫低下患者疾病的分子机制。这可能会导致开发新的治疗措施来治疗IA。这一建议有三个特定的目的，旨在确定由类固醇调节元件结合蛋白(SREBP)介导的低氧适应的分子机制，SRbA介导低氧适应和真菌毒力。在目标1中，我们将确定srbA在烟曲霉菌中被激活的地点和时间，建立srbA介导的烟曲霉菌低氧适应模型的第一部分。在目标2中，我们将识别和描述与srbA相互作用的关键角色，并可能调控其活动，为我们的模型增加第二个监管层。在目标3中，将确定和表征介导烟曲霉菌对低氧适应的srbA的关键下游效应因子。这三个目标的完成将为了解烟曲霉一种新的毒力属性的机制提供必要的见解，并首次为在致病霉菌中建立SREBP信号模型奠定基础。对这些特定目标的研究也将为未来的研究提供更多的靶点，以阐明可能适用于广泛致病霉菌的低氧适应机制。与公共卫生相关：随着医疗技术的进步，由常见霉菌引起的致命感染正变得越来越普遍。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。这项建议寻求发现新的治疗方案来治疗由丝状霉菌烟曲霉菌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.