The inactive X: discovering sex genes that influence female vulnerability to Alzheimer's disease

不活跃的X：发现影响女性易患阿尔茨海默病的性基因

• 批准号: 10471087
• 负责人: Rachel Frances Buckley
• 金额: $ 151.2万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10471087
• 关键词: Address; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Autoimmune Diseases; Automobile Driving; Biological; Blood; Brain region; Cells; Chromosomes; Clinical; Clinical Trials; Collaborations; Disease; Drug Targeting; Epigenetic Process; Evaluation; Exhibits; Female; Foundations; Genes; Genetic; Genetic Diseases; Genomics; Gonadal Steroid Hormones; Hormonal Change; Human; Immune response; Immune system; Inflammatory; Link; Literature; Measurement; Memory; Menopause; Nerve Degeneration; Neurodegenerative Disorders; Outcome; Overdose; Pathologic; Pathology; Pathway interactions; Phenotype; Play; Positron-Emission Tomography; Predisposition; Reporting; Risk; Role; Sampling; Sex Chromosomes; Sex Differences; Techniques; Tissues; Woman; X Chromosome; X Inactivation; aging brain; asymptomatic Alzheimer' s disease; biological sex; cohort; data harmonization; drug response prediction; genome sequencing; hormone therapy; in vivo; inflammatory marker; innovation; men; neuroimaging; neuroimaging marker; neuroinflammation; novel; novel strategies; older women; religious order study; sex; skills; statistics; tau Proteins; transcriptome sequencing; transcriptomics; whole genome

PROJECT SUMMARY Of the two hallmark proteinopathies, b-amyloid and tau, that define Alzheimer’s disease (AD), studies consistently show that women exhibit higher levels of tau than men. This finding is well-characterized in older women, even those who are considered clinically normal, but the biological mechanism driving this sex difference remains elusive. Sex hormonal changes, either due to menopause or hormone therapy, may be a contributing factor, although effects are equivocal. Sex hormones are not the only sex biological component that could play a role. Sex chromosomes form the genetic foundation by which women are biologically differentiated from men. The X chromosome, in particular, has largely been ignored in the AD field, due to complexities involving measurement and analysis. Women possess two X chromosomes, which has profound implications for sex-specific associations with neurodegenerative disease. To avoid ‘overdosing’ women with X-linked genes coming from two X chromosomes, one X is randomly silenced in each cell throughout the body. This random X inactivation, however, is incomplete, with some genes escaping this inactivation. In human women, approximately 30% of X-linked genes consistently escape inactivation across all tissue types. Of those inactive X escaped genes that have been reported in the literature (n=60), many are involved in the immune system. Due to this phenomenon, women tend to exhibit more robust immune systems and are more likely to suffer from autoimmune diseases. Of relevance to AD, neuroinflammation, exacerbated by robust immune responses, is argued to be a key early driver of pathology in vulnerable brain regions. These key pieces of evidence give rise to an innovative question that has never been tackled: could inactive X escaped genes be the key to explaining female vulnerability to AD pathology? And could this mechanism occur via an inflammatory pathway? As such, in this innovative proposal I put forward a conceptually novel approach to addressing sex differences in AD pathology by focusing on the ‘eXcluded’ chromosome. In collaboration with expert colleagues in the field of AD genetics, I will employ the latest techniques to examine the genomic, transcriptomic, and epigenetic impact of inactive-X escaped genes as a driver of sex differences in in vivo neuroimaging markers of b-amyloid and tau. This study will be unparalleled in its scope, as I will leverage my skills in neuroimaging, data harmonization and statistics to combine three large, deeply-phenotyped cohorts that have b-amyloid and tau positron emission tomography neuroimaging and samples for whole genome and transcriptome sequencing (n=900) and pro-inflammatory markers in blood: the Harvard Aging Brain Study (HABS), the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) study. I will also validate my findings in the Religious Orders Study, the Memory and Aging Project (ROS/MAP) and the Alzheimer’s disease Neuroimaging Initiative (ADNI). Elucidating sex-specific mechanisms for AD risk has far-reaching consequences for identifying drug targets, but also better predicting drug response outcomes in men and women in clinical trials.

项目概要 研究表明，b-淀粉样蛋白和 tau 蛋白这两种定义阿尔茨海默病 (AD) 的标志性蛋白病 一致表明，女性的 tau 蛋白水平高于男性，这一发现在老年人中很明显。 女性，即使是那些临床上被认为正常的女性，但驱动这种性别的生物机制 由于更年期或激素治疗，性激素的变化可能是一种差异。 性激素并不是唯一的性生物学成分，但其​​影响尚不明确。 性染色体构成了女性生物学的遗传基础。 特别是 X 染色体与男性的区别在 AD 领域很大程度上被忽视了。 涉及测量和分析的复杂性。女性拥有两条 X 染色体，其意义深远。 避免对患有神经退行性疾病的女性进行“过量用药”。 X连锁基因来自两条X染色体，其中一条X在全身每个细胞中随机沉默。 然而，这种随机的 X 失活是不完整的，一些基因在人类中逃脱了这种失活。 女性中，大约 30% 的 X 连锁基因在所有组织类型中始终逃脱失活。 文献报道的不活跃的X逃逸基因（n=60），许多与免疫有关 由于这种现象，女性往往表现出更强大的免疫系统，并且更有可能。 患有与 AD 相关的自身免疫性疾病，神经炎症，并因强大的免疫而加剧。 反应被认为是脆弱大脑区域病理学的关键早期驱动因素。 证据提出了一个从未得到解决的创新问题：不活跃的 X 逃逸基因是否可以被解决？ 解释女性易患AD病理的关键是什么？这种机制是否可以通过某种机制发生？ 因此，在这个创新提案中，我提出了一种概念上新颖的方法 通过关注“排除”染色体来解决 AD 病理学中的性别差异。 AD遗传学领域的专家同事们，我将采用最新的技术来检查基因组， 非活性X逃逸基因的转录组和表观遗传影响作为体内性别差异的驱动因素 B-淀粉样蛋白和 tau 蛋白的神经影像标记物这项研究的范围将是无与伦比的，因为我将利用我的研究成果。 神经影像、数据协调和统计方面的技能，将三个大型、深度表型的群体结合起来 具有 b-淀粉样蛋白和 tau 正电子发射断层扫描神经影像和全基因组样本 转录组测序（n=900）和血液中的促炎标记物：哈佛大脑老化研究 (HABS)、无症状阿尔茨海默氏症的抗淀粉样蛋白治疗 (A4) 研究和纵向评估 我还将在宗教团体中验证我的研究结果。 研究、记忆与衰老项目 (ROS/MAP) 和阿尔茨海默病神经影像计划 (ADNI)。 阐明 AD 风险的性别特异性机制对于确定药物靶点具有深远的影响， 而且还可以在临床试验中更好地预测男性和女性的药物反应结果。