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

抽象的。 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，这一数字将超过癌症，成为头号死因。然而，预防、治愈或 甚至治疗AD/ADRD都没有成功。遗传、血液和核磁共振生物标记物可用于风险评估 分层，但对于高危人群来说，改善疾病的选择有限。此外，虽然种族 AD/ADRD患病率的差异已被报道，少数族裔群体的患者经常 诊断延迟或治疗选择不足。因此，需要努力确定可更改的风险因素。 这可能会将处于危险中的人群分层，逆转疾病进程，并确定新的生物标志物 未被充分研究的种群。 肠道微生物区系是一种可改变的危险因素，已被证明与中枢神经系统相互作用。 通过双向肠道-微生物区系-脑轴，从而影响大脑的生理和病理。在这 申请K01奖项，伯纳德·丰冈博士，格伦·比格斯阿尔茨海默氏症研究所的生物信息学家 神经退行性疾病和南得克萨斯州阿尔茨海默病研究中心将利用数据 来自两个队列，以研究肠道微生物群和AD/ADRD内表型之间的关联。在AIM 1，他将研究肠道微生物区系特征(细菌丰度和多样性)是否与各种 AD/ADRD的神经成像和神经认知标记物，使用Framingham心脏研究和 德克萨斯州阿尔茨海默氏症研究和护理联盟(TARCC)。在目标2中，方刚博士将评估血浆 这些标记物的代谢组学特征。最后，在目标3中，他将使用整合的组学方法和复杂的 用于识别与神经成像和神经成像相关的微生物衍生代谢物的数学模型 ADRD的神经心理标记物及其与AD事件的关系。很大比例的 TARCC研究人群中的拉美裔也将允许检查种族和性别的差异。这个 这项研究的结果将作为R01赠款申请的基础，该申请将于#年第3年完成 获奖。 除了为这项创新和重要的研究提供资金外，这款K01将为方刚博士提供 实现他成为独立资助的新生物学研究领导者的目标所需的支持 和新的药物靶点，以加快ADRD的药物开发。方刚博士召集了一位导师 由比格斯研究所创始主任苏达·塞沙德里博士担任主要导师的团队，以及三名 共同导师：约瑟夫·彼得罗西诺博士，人类微生物组专家；Patrick Sung博士，生物化学和 具有丰富指导经验的结构生物学；以及脂肪组学和 代谢组学。在与他的指导团队的合作下，他还制定了一份详细的课程计划 以及帮助他实现研究和职业目标的读物。

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.