Investigation on Replicative aging in Cryptococcus neoformans populations

新型隐球菌种群复制衰老的研究

基本信息

批准号：
9366305
负责人：
Bettina Fries
金额：
$ 68.78万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-27 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9366305
关键词：
Acquired Immunodeficiency Syndrome Affect Age Age Distribution Aging Aging-Related Process Antifungal Agents Antifungal Therapy Applications Grants Biology Biomedical Engineering Cell Extracts Cell Wall Cell division Cells Cerebrospinal Fluid Chitin Chronic Clinical Communicable Diseases Complex Cryptococcus neoformans Cryptococcus neoformans infection Discipline Disease Disease Outcome Environment Faculty Funding Fungal Drug Resistance Generations Glucans Heterogeneity Host Defense Human Hydrogen Peroxide In Vitro Infection Investigation Lead Lipids Longevity Mass Spectrum Analysis Medicine Meningoencephalitis Mentors Methodist Church Methods Microbe Microbiology Microdissection Microfluidics Modeling Morbidity - disease rate Mycoses Pathogenesis Pathogenicity Patients Phagocytosis Pharmacotherapy Phenotype Population Process Progressive Disease Property Rattus Reproducibility Research Research Institute Research Proposals Resistance Resveratrol Saccharomyces cerevisiae Stress System Techniques Testing Universities Variant Virulence Yeasts age related base efficacy testing fitness fungus graduate student high throughput screening in vivo killings macrophage mathematical model member mortality mutant nanomedicine novel novel therapeutics pathogen pressure resilience stressor trait transcriptome

项目摘要

This application deals with a general problem in virulence of how pathogenic microbes adapt to and/or escape host defenses and persist. Most infections are characterized by a complex relationship between the host and the pathogen referred to as pathoadaptation. The system under study is based on Cryptococcus neoformans (CN), a human pathogenic fungus that is a major cause of mortality and morbidity in AIDS patients. This fungal infection is notoriously difficult to treat and despite effective antifungal therapy mortality is high especially in AIDS patients with progressive disease. In the course of a R21 funded research proposal we determined that replicating CN cells undergo asymmetric cell divisions a process that leads to generational or replicative aging. CN cells undergo a finite number of divisions before they die. The replicative life span (RLS) of a CN strain is a reproducible trait that can be determined through micro-dissection. We found that CN cells of advanced replicative age (older) persist during chronic infection because they are more resistant to hydrogen peroxide stress, macrophage intracellular killing, and antifungal agents. We now propose to investigate the process of replicative aging in more detail and specifically elucidate how the emerging properties of aging lead to selection of older CN cells in the host, and contribute to persistence and virulence. Our proposal is divided in three aims: I.) To investigate RLS dynamics in CN strains ii.) To investigate why old CN cells are more resistant to antifungals and phagocytosis iii.) To investigate and model age dependent resilience and vulnerability in vitro and in vivo.

本申请涉及病原微生物如何适应和/或逃脱宿主防御并坚持下去。大多数感染都具有复杂的关系宿主与病原体之间的适应称为路径适应。所研究的系统基于新型隐球菌（CN）是一种人类致病真菌，是导致死亡和死亡的主要原因艾滋病患者的发病率。这种真菌感染是出了名的难以治疗，尽管有效抗真菌治疗死亡率很高，尤其是病情进展的艾滋病患者。在课程中在 R21 资助的研究计划中，我们确定复制 CN 细胞会经历不对称细胞分裂是导致世代或复制衰老的过程。 CN 细胞经历有限次数的死前的分裂。 CN 菌株的复制寿命 (RLS) 是一种可重复的特征，可以通过显微解剖来确定。我们发现复制年龄较高（较老）的 CN 细胞在慢性感染期间持续存在，因为它们对过氧化氢应激具有更强的抵抗力，巨噬细胞胞内杀伤剂和抗真菌剂。我们现在建议调查这个过程更详细地描述复制性衰老，并具体阐明衰老的新特性如何导致选择宿主中较老的 CN 细胞，并有助于持久性和毒力。我们的建议是分为三个目标： I.) 研究 CN 菌株中的 RLS 动态 ii.) 研究为什么老 CN 细胞对抗真菌药物和吞噬作用更具抵抗力 iii.) 研究年龄依赖性并建立模型体外和体内的弹性和脆弱性。