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.

该应用程序涉及致病微生物如何适应和/或逃避主机防御并坚持下去。大多数感染的特征是复杂的关系在宿主和病原体之间称为病原体。研究的系统是基于的关于隐孢子虫（CN），一种人类的致病真菌，是死亡率和死亡率的主要原因艾滋病患者的发病率。众所周知，这种真菌感染很难治疗，尽管有效抗真菌治疗的死亡率很高，特别是在患有进行性疾病的艾滋病患者中。在课程中在R21资助的研究建议中，我们确定复制CN细胞发生不对称细胞分裂导致世代或复制衰老的过程。 CN单元经历有限数量的分裂死前。 CN菌株的复制寿命（RLS）是一种可再现的特征可以通过微截断来确定。我们发现高级复制年龄的CN细胞（较老）在慢性感染期间持续存在，因为它们对过氧化氢应激更具耐药性，巨噬细胞内杀害和抗真菌药物。我们现在建议调查更详细的复制衰老，特别阐明了衰老的新出现特性如何导致选择宿主中较旧的CN细胞，并有助于持久性和毒力。我们的建议是分为三个目的：I。）研究CN菌株中的RLS动力学II。）研究为什么旧的CN细胞对抗真菌和吞噬作用更具耐药性III。体外和体内的弹性和脆弱性。