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。 阿尔茨海默病（AD）和AD相关痴呆（AD/ADRD），全球患病率为50 到2040年，2018年将超过癌症，成为死亡的主要原因。然而，预防、治疗或 即使治疗AD/ADRD也不成功。遗传、血液和MRI生物标志物可用于风险评估 分层，但对于那些处于高风险的人来说，疾病修饰的选择有限。此外，虽然种族 据报道，AD/ADRD患病率存在差异，少数民族患者经常接受 诊断延迟或治疗选择不足。因此，需要努力查明可改变的风险因素 这可以对高危人群进行分层，逆转疾病进程，并确定新的生物标志物， 研究不足的人群。 肠道微生物群是一种可改变的风险因素，已被证明与中枢神经系统相互作用 通过双向肠道-微生物群-脑轴，从而影响脑生理学和病理学。在这 申请K 01奖，伯纳德博士Fongang，生物信息学家在格伦比格斯研究所阿尔茨海默氏症 南德克萨斯阿尔茨海默病研究中心将利用数据 研究肠道微生物组与AD/ADRD内表型之间的关联。在Aim中 1，他将研究肠道微生物群特征（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志物，使用来自心脏研究和 得克萨斯州阿尔茨海默氏症研究和护理联盟（TARCC）。在目标2中，Fongang博士将评估血浆 这些标记的代谢组学特征。最后，在目标3中，他将使用综合组学方法和复杂的 数学模型，以确定与神经成像相关的微生物衍生的代谢物， ADRD的神经心理学标志物以及它们如何与AD事件相关联。很大比例的 TARCC研究人群中的西班牙裔也将允许检查种族和性别的差异。的 这项研究的结果将作为R 01赠款申请的基础，将在2010年的第3年完成。 奖 沿着这项创新和重要研究的资金，K 01将为Fongang博士提供 他的目标是成为一个独立资助的领导者，在确定新的生物学 和新的药物靶点，以加速ADRD的药物开发。方刚博士召集了一个 团队由比格斯研究所的创始主任Sudha Seshadri博士作为主要导师， 共同导师：Joseph Petrosino博士，人类微生物组专家;帕特里克宋博士，生物化学和 具有丰富指导经验的结构生物学;以及脂质组学专家和 代谢组学在与他的指导团队合作，他还制定了详细的课程计划 和阅读，以帮助他实现他的研究和职业为基础的目标。