Pathogenesis of Polymicrobial Cerebritis-Related Dementia

多种微生物脑炎相关痴呆的发病机制

• 批准号: 10119639
• 负责人: DAVID B CORRY
• 金额: $ 32.08万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-23 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10119639
• 关键词: Adherence; Adhesions; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease related dementia; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Area; Asthma; Bacteria; Blood - brain barrier anatomy; Blood Circulation; Brain; Candida albicans; Caring; Cause of Death; Cerebritis; Cerebrum; Chronic; Dementia; Deposition; Diagnosis; Elderly; Endothelial Cells; Endothelium; Enteral; Enterobacteriaceae; Epidemiology; Epithelial; Epithelium; Etiology; Event; Future; Gastrointestinal tract structure; Gliosis; Granuloma; Hematogenous; Hematogenous Spread; Human; Hyphae; Immune; In Vitro; Infection; Infectious Agent; Intestines; Intravenous; Laboratories; Link; Lytic; Mediating; Medical; Memory; Metagenomics; Modeling; Mucous Membrane; Mus; Mycoses; Nerve Degeneration; Oral; Parents; Pathogenesis; Peptides; Plant Roots; Research; Role; Route; Senile Plaques; Source; Surface; Tauopathies; Testing; Virulence Factors; Wild Type Mouse; Yeasts; base; brain circulation; brain parenchyma; cost estimate; enteritis; fecal microbiome; fungus; gut microbiota; human disease; in vivo; inflammatory lung disease; intravenous injection; mouse model; prevent; statistics

The broad, long-term objectives of my laboratory are to understand the immune and environmental basis of inflammatory lung diseases such as asthma and the broader role of these etiologic factors in human disease. Inexplicably, Alzheimer's disease (AD), the most common cause of dementia and the 5th leading cause of death among elderly Americans, is epidemiologically linked to asthma, suggesting the existence of a shared etiologic factor. AD is the only one among the top 10 causes of death that cannot be prevented, slowed, or cured. AD is already the most expensive medical condition in the US, with total costs estimated at $200 billion, but this is expected to rise to an astonishing $1 trillion by 2050 if improvements in medical care are not found. Despite these alarming statistics and decades of research, the fundamental cause of AD and related dementias remains unknown. As we have previously shown, asthma in many cases is due to airway mycosis, a superficial infection of the airway mucosa involving diverse fungi. This discovery is the central observation in our parent application AI135803. Furthermore, AD has been linked to polymicrobial brain infections based on the discovery of fungi, especially the yeast Candida albicans, and a variety of bacteria in the brains of those suffering from AD. The premise of this application is therefore that low-grade polymicrobial brain infections involving C. albicans and bacteria potentially deriving from the gastrointestinal (GI) tract could be a root cause of AD and potentially other chronic neurodegenerative conditions. Our preliminary studies demonstrated that C. albicans induces canonical features of AD, providing in vivo support of the concept that fungal infection may underlie AD in some subjects. Our additional studies now show that C. albicans when administered to mice through the oral route escape the GI tract and enter the mouse brain together with numerous bacteria, producing a polymicrobial, fungus-centered cerebritis. Nonetheless, definitive evidence of a fungal infectious etiology in AD is lacking. We therefore hypothesize that GI tract infection with C. albicans spreads hematogenously to the brain together with enteric bacteria to establish polymicrobial brain infections. To test this hypothesis, we propose the following Aims: Aim 1. To determine the origin and identity of bacteria associated with polymicrobial cerebral mycosis (C. albicans + bacteria). Aim 2. To determine the mechanism by which C. albicans and bacteria establish polymicrobial brain infections. Together, these aims will elucidate the possible contribution of environmental fungi and bacteria to the pathogenesis of polymicrobial brain infections previously linked to AD.

我的实验室的广泛的，长期的目标是了解免疫和环境的基础， 炎症性肺病如哮喘和这些病因因素在人类疾病中的更广泛作用。 令人费解的是，阿尔茨海默病（AD），痴呆症的最常见原因和第五大原因， 在流行病学上，美国老年人的死亡与哮喘有关，这表明存在一种共同的 病因AD是十大死亡原因中唯一无法预防、减缓或 痊愈了AD已经是美国最昂贵的医疗条件，总成本估计为2000亿美元， 但如果医疗保健得不到改善，预计到2050年这一数字将上升到惊人的1万亿美元。 尽管有这些令人震惊的统计数据和数十年的研究，AD的根本原因和相关的 痴呆症仍然未知。正如我们先前所示，在许多情况下，哮喘是由于气道真菌病， 一种涉及多种真菌的呼吸道粘膜的浅表感染。这一发现是 我们的父应用程序AI135803。此外，AD与多种微生物脑感染有关， 真菌的发现，特别是酵母菌白色念珠菌，以及各种细菌在大脑中的那些 患AD。因此，这种应用的前提是， 涉及C.可能来自胃肠道的白色念珠菌和细菌可能是根本原因 AD和潜在的其他慢性神经退行性疾病。我们的初步研究表明，C。 白色念珠菌诱导AD的典型特征，为真菌感染可能 在某些科目中是AD的基础。我们的进一步研究表明，C。当给予小鼠时， 通过口服途径逃离胃肠道并与大量细菌一起进入小鼠大脑， 导致多微生物真菌性脑炎尽管如此，真菌感染的确切证据 缺乏AD的病因学。因此，我们假设胃肠道感染C。白色念珠菌播散 血液生成性地与肠道细菌一起进入脑以建立多微生物脑感染。测试 根据这一假设，我们提出以下目标：目标1。确定细菌的来源和身份 与多微生物脑真菌病（C.白色念珠菌+细菌）。目标2.为了确定机制 其中C.白色念珠菌和细菌造成多微生物脑感染。总之，这些目标将阐明 环境真菌和细菌对多微生物脑发病机制的可能贡献 以前与AD有关的感染。