Delineating the role of the gut microbiota and its derived metabolites in the development of dementia in multi-ethnic populations

描述肠道微生物群及其衍生代谢物在多种族人群痴呆症发展中的作用

• 批准号: 10592025
• 负责人: Bernard Fongang
• 金额: $ 22.04万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10592025
• 关键词: 16S ribosomal RNA sequencing; Acceleration; Address; Affect; Age-associated memory impairment; Alzheimer' s Disease; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer' s disease therapy; Anti-Inflammatory Agents; Applications Grants; Award; Bacteria; Bacteroides; Biochemistry; Bioinformatics; Biology; Blood; Blood - brain barrier anatomy; Brain; Caring; Cause of Death; Central Nervous System; Chronology; Collaborations; Communication; Data; Dementia; Dependence; Development; Diagnosis; Diet; Disease; Episodic memory; Escherichia; Ethnic Origin; Ethnic Population; Etiology; Foundations; Framingham Heart Study; Functional disorder; Funding; Future; Genetic; Goals; Hispanic Populations; Human Microbiome; Individual; Inflammatory; Infrastructure; Learning; Link; Longitudinal Studies; Magnetic Resonance Imaging; Malignant Neoplasms; Mass Spectrum Analysis; Measures; Memory; Mentored Research Scientist Development Award; Mentors; Metabolic; Metabolism; Methods; Microvascular Dysfunction; Modeling; Neurocognitive; Neurodegenerative Disorders; Neuropsychology; Not Hispanic or Latino; Nutrient; Obesity; Outcome Measure; Pathogenicity; Pathology; Pharmaceutical Preparations; Physiology; Plasma; Population; Populations at Risk; Prevalence; Prevotella; Reporting; Research; Risk Factors; Role; Sex Differences; Shigella; Signal Transduction; South Texas; Structure; Testing; Texas; Therapeutic; Thinking; Time; bacterial community; bacterial metabolism; brain health; career; cerebral atrophy; cohort; drug development; endophenotype; ethnic difference; ethnoracial minority; executive function; experience; fecal microbiota; gut dysbiosis; gut microbes; gut microbiome; gut microbiota; high risk; innovation; insight; interest; lipidomics; magnetic resonance imaging biomarker; mathematical model; metabolome; metabolomics; microbial; microbial community; microbiome; microbiota; microbiota metabolites; microbiota-gut-brain axis; mild cognitive impairment; minority patient; modifiable risk; multi-ethnic; neuroimaging; neuroimaging marker; new therapeutic target; novel; novel marker; novel strategies; population stratification; prevent; processing speed; public health relevance; response; risk stratification; sex; structural biology; study population; systemic inflammatory response; targeted treatment; visual memory; white matter

Abstract. Alzheimer's disease (AD) and AD-related dementias (AD/ADRD), with a worldwide prevalence of 50 million in 2018, will surpass cancer as the leading cause of death by 2040. However, efforts to prevent, cure, or even treat AD/ADRD have been unsuccessful. Genetic, blood, and MRI biomarkers can be used for risk stratification, but there are limited disease-modifying options for those at high risk. Moreover, while ethnic differences in AD/ADRD prevalence have been reported, patients of minority ethnoracial groups often receive delayed diagnosis or inadequate treatment options. Thus, efforts are needed to identify modifiable risk factors that could stratify the population at risk, reverse the disease course, and determine novel biomarkers for understudied populations. The gut microbiota, a modifiable risk factor, has been shown to interact with the central nervous system through the bidirectional gut-microbiota-brain axis and thus, affecting brain physiology and pathology. In this application for a K01 award, Dr. Bernard Fongang, a Bioinformatician at the Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases and the South Texas Alzheimer's disease Research Center will leverage data from two cohorts to study the association between the gut microbiome and AD/ADRD endophenotypes. In Aim 1, he will examine whether the gut microbiota features (bacteria abundance and diversity) are related to various neuroimaging and neurocognitive markers of AD/ADRD, using data from the Framingham Heart Study and the Texas Alzheimer's Research and Care Consortium (TARCC). In Aim 2, Dr. Fongang will assess the plasma metabolomics profiles of these markers. Finally, in Aim 3, he will use integrative omics methods and sophisticated mathematical models to identify the microbiota-derived metabolites related to neuroimaging and neuropsychological markers of ADRD and how they are linked with incident AD. The large proportion of Hispanics within the TARCC study population will also allow for examining differences by ethnicity and sex. The results of this study will serve as the foundation for an R01 grant application, to be completed by year 3 of the award. Along with funding for this innovative and important research, this K01 will provide Dr. Fongang with the support necessary to achieve his goal of becoming an independently-funded leader in identifying novel biology and novel drug targets to accelerate drug development for ADRD. Dr. Fongang has assembled a mentoring team comprised of Dr. Sudha Seshadri, founding director of the Biggs Institute, as the primary mentor, and three co-mentors: Dr. Joseph Petrosino, an expert in human microbiome; Dr. Patrick Sung, Chair of Biochemistry and structural biology with extensive mentoring experience; and Dr. Xianlin Han, an expert in lipidomics and metabolomics. In collaboration with his mentoring team, he has also developed a detailed plan of coursework and readings to help him achieve his research- and career-based goals.

抽象的。 阿尔茨海默氏病（AD）和与AD相关的痴呆症（AD/ADRD），全球患病率为50 2018年的百万人将在2040年到达癌症作为死亡的主要原因。但是，预防，治愈或 甚至待遇广告/adrd都没有成功。遗传，血液和MRI生物标志物可用于风险 分层，但是对于高风险的人来说，疾病改良的选择有限。而且，虽然种族 据报道，AD/ADRD患病率的差异，少数民族群体的患者经常接受 诊断延迟或治疗选择不足。因此，需要努力来确定可修改的风险因素 这可能会使处于危险中的人口分层，扭转疾病的病程，并确定新颖的生物标志物 研究的人口。 肠道菌群是一种可修改的危险因素，已显示与中枢神经系统相互作用 通过双向肠道微生物脑轴，从而影响脑生理和病理学。在这个 K01奖的申请，Glenn Biggs阿尔茨海默氏症研究所的生物信息学家Bernard Fongang博士 和神经退行性疾病和南德克萨斯州阿尔茨海默氏病研究中心将利用数据 从两个队列研究肠道微生物组与AD/ADRD内表型之间的关联。目标 1，他将检查肠道菌群特征（细菌丰度和多样性）是否与各种 AD/ADRD的神经影像学和神经认知标记，使用Framingham心脏研究和 德克萨斯州阿尔茨海默氏症研究与护理联盟（TARCC）。在AIM 2中，Fongang博士将评估血浆 这些标记的代谢组学概况。最后，在AIM 3中，他将使用整合的OMICS方法和精致 数学模型，以识别与神经影像学和神经影像有关的微生物源代谢产物 ADRD的神经心理标记及其与事件广告的联系方式。大部分 TARCC研究人群中的西班牙裔人也将通过种族和性别来检查差异。这 这项研究的结果将作为R01赠款申请的基础，将在第3年完成 奖。 除了为这项创新和重要研究的资助外，该K01还将为Fongang博士提供 实现他成为独立资助的领导者确定新型生物学所必需的支持 和新的药物靶标，以加速ADRD的药物开发。 Fongang博士聚集了指导 团队由Biggs Institute的创始董事Sudha Seshadri博士组成，主要导师，三位 联合官员：人类微生物组专家约瑟夫·佩特罗西诺（Joseph Petrosino）博士；生物化学主席帕特里克·昂格（Patrick Sung）博士 结构生物学具有丰富的指导经验； Xianlin Han博士，脂肪态学专家和 代谢组学。与他的指导团队合作，他还制定了详细的课程计划 和读物以帮助他实现基于研究和职业的目标。