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。侵入性曲霉菌病（IA）是免疫疾病中传染性发病和死亡率的主要原因患者，尤其是患有急性白血病，造血细胞移植的患者和慢性病患者皮质类固醇治疗用于移植物与宿主疾病和自身免疫性。尽管最近的抗真菌进展疗法，哪些真菌和宿主因素对于疾病进展至关重要，在在肺部建立感染。我们已经对缩小这一点进行了2个基本观察知识差距。首先，IA的病因，曲霉的烟曲霉与宿主组织相互作用以产生A 感染部位的动态氧微环境。第二，烟曲霉适应已建立的感染微环境通过表现出对真菌病毒至关重要的感染特异性代谢灵活性。我们最近称这些适应为“疾病进展因素”（DPF），因为它们对于在人类真菌感染的背景下，侵入性疾病的进展和相对不确定。令人兴奋的最近的发现是真菌氧反应遗传网络的先前未欣赏的作用，包括DPF，SRBA，SRBB和CREA，对氧张力的过渡响应。我们最近的数据负责人我们假设这种氧反应网络调节了特定代谢产物的产生促进和支持真菌疾病进展。这个遗传网络的主要效应子，一种未研究的真菌丙氨酸氨基转移酶ALAA是本提案目标1的机械研究重点。我们提出了一个 ALAA充当适应氧所需的代谢过渡的关键调节剂的模型真菌疾病进展过程中的波动。在AIM 2中，我们建立了一个具有新颖的遗传屏幕确定了四个新的未研究的真菌转录因子，这对于对氧气张力的反应至关重要波动。我们为氧气响应真菌转录因子命名了这些新基因ORTA-D。一个对我们测试假设和模型的方法的创新是纳入体内成像疾病进展过程中感染部位的微环境正在揭示对真菌形式的新见解和在已建立的感染中起作用。因此，在这些研究的结论中，我们将定义新的在已建立的感染环境中真菌适应性的分子机制，这些环境有望揭示新的这些经常致命的侵入性霉菌感染的治疗机会可以改善疾病结局。