Environmental Oxygen Transitions and Aspergillosis Disease Progression

环境氧转变和曲霉病进展

基本信息

批准号：
10404535
负责人：
Robert Andrew Cramer
金额：
$ 52.94万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10404535
关键词：
Acute leukemia Adrenal Cortex Hormones Alanine Transaminase Antifungal Agents Antifungal Therapy Aspergillosis Aspergillus fumigatus Autoimmunity Chronic Collection Data Defect Development Disease Disease Outcome Disease Progression Dose Environment Exhibits Fungal Genes Genes Genetic Genetic Screening Genetic Transcription Growth Health Homeostasis Human Hypoxia Immune Infection Integration Host Factors Knowledge Lead Lung Metabolic Metabolism Microbial Biofilms Modeling Molds Molecular Morbidity - disease rate Mycoses Names Natural Immunity Oxygen Pathway interactions Patients Phenotype Production Regulation Research Role Site Testing Tissues Transplant Recipients Virulence Work base chemotherapy fitness flexibility fungus genetic effector graft vs host disease hematopoietic cell transplantation improved in vivo in vivo imaging innovation insight metabolome mortality mutant novel novel therapeutics pathogenic fungus patient population response therapeutic target transcription factor transcriptome

项目摘要

Project Summary. Invasive aspergillosis (IA) is a major cause of infectious morbidity and mortality in immune compromised patients, particularly those with acute leukemia, hematopoietic cell transplantation, and recipients of chronic corticosteroid therapy for graft versus host disease and autoimmunity. Despite recent advances in antifungal therapies, it remains poorly understood which fungal and host factors are critical for disease progression after establishment of infection in the lung. We have made 2 fundamental observations toward narrowing this knowledge gap. First, the causative agent of IA, Aspergillus fumigatus, interacts with host tissue to generate a dynamic oxygen microenvironment at the site of infection. Second, A. fumigatus adapts to established infection microenvironments by exhibiting infection site-specific metabolic flexibility that is critical for fungal virulence. We recently termed these adaptations “disease progression factors” (DPFs) because they are essential for the progression of invasive disease and relatively undefined in the context of human fungal infections. An exciting recent discovery is the previously unappreciated role of the fungal oxygen response genetic network, which includes the DPFs, SrbA, SrbB and CreA, in responses to transitions in oxygen tension. Our recent data lead us to hypothesize that this oxygen response network regulates the production of specific metabolites that promote and support fungal disease progression. A major effector of this genetic network, an unstudied fungal alanine aminotransferase alaA, is the focus of mechanistic studies in Aim 1 of this proposal. We propose a model whereby alaA functions as key regulator of metabolic transitions required for adaptation to oxygen fluctuations during fungal disease progression. In aim 2, we build off a novel genetic screen which has identified four new unstudied fungal transcription factors that are critical for the response to oxygen tension fluctuations. We have named these new genes ortA-D for oxygen responsive fungal transcription factors. An innovation to our approach to test our hypotheses and models is the incorporation of in vivo imaging of the infection site microenvironment during disease progression that is revealing new insights into fungal form and function in an established infection. Consequently, at the conclusion of these studies, we will have defined new molecular mechanisms of fungal fitness in established infection environments that are expected to reveal new therapeutic opportunities to improve disease outcomes for these too often lethal invasive mold infections.

项目摘要。侵袭性曲霉病 (IA) 是免疫受损者感染发病和死亡的主要原因患者，特别是患有急性白血病、造血细胞移植和慢性病接受者尽管抗真菌药物最近取得了进展，但皮质类固醇治疗移植物抗宿主病和自身免疫性疾病。治疗后，人们对哪些真菌和宿主因素对于疾病进展至关重要仍知之甚少。为了缩小这一范围，我们进行了两项基本观察。首先，IA 的病原体烟曲霉与宿主组织相互作用，产生一种其次，烟曲霉适应已建立的感染。通过表现出对真菌毒力至关重要的感染位点特异性代谢灵活性来改变微环境。我们最近将这些适应称为“疾病进展因子”（DPF），因为它们对于人类真菌感染背景下侵袭性疾病和相对不确定的进展。最近的发现是真菌氧反应遗传网络的先前未被认识到的作用，包括 DPF、SrbA、SrbB 和 CreA，以响应我们最近的数据领先。我们发现这个氧反应网络调节特定代谢物的产生促进和支持真菌疾病的进展是该遗传网络的主要效应器，是一种未经研究的真菌。丙氨酸氨基转移酶alaA是本提案目标1中机制研究的重点，我们提出了一个。 alaA 作为适应氧气所需的代谢转变的关键调节因子的模型在目标 2 中，我们建立了一种新颖的基因筛查，该筛查具有以下特点：确定了四种新的未经研究的真菌转录因子，它们对于氧张力的反应至关重要我们将这些新基因命名为 ortA-D，表示氧响应真菌转录因子。我们测试假设和模型的方法的创新在于结合了体内成像疾病进展期间感染部位的微环境揭示了对真菌形式和在这些研究结束时，我们将定义新的感染的功能。已建立的感染环境中真菌适应性的分子机制有望揭示新的改善这些往往致命的侵入性霉菌感染的疾病结果的治疗机会。