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.

项目摘要 在定义阿尔茨海默氏病（AD）的两种标志性蛋白质病，B-淀粉样蛋白和TAU中 一贯表明，女性表现出比男性更高的tau水平。这一发现在较旧的 妇女，甚至那些被认为在临床上正常的人，但是驱动这种性别的生物学机制 差异仍然难以捉摸。性激素改变是由于更年期或马酮治疗，可能是 促成因素，尽管效果是等效的。性激素不是唯一的性生物学成分 那可以发挥作用。性染色体构成了女性在生物学上是遗传基础 与男人区分开。尤其是X染色体，由于广告字段中的大部分被忽略了 涉及测量和分析的复杂性。女性拥有两个X染色体，具有深刻的 与神经退行性疾病的性别特异性关联的影响。避免与 X连锁基因来自两个X染色体，一个X在整个体内的每个细胞中随机沉默。 然而，这种随机的X失活是不完整的，某些基因逃脱了这种失活。在人类中 女性，约有30％的X连锁基因始终逃脱所有组织类型的失活。那些 在文献中报道的非活性X逃脱基因（n = 60），许多参与免疫 系统。由于这种现象，女性倾向于表现出更健壮的免疫系统，并且更有可能 患有自身免疫性疾病。与AD，神经炎症相关，可通过可靠的免疫加剧 反应被认为是脆弱的大脑区域病理学的主要早期驱动力。这些关键部分 证据引起了一个从未解决过的创新问题：不活跃的X逃脱基因可能是 解释女性脆弱性AD病理学的关键？并且这种机制可能通过 炎症途径？因此，在这个创新的建议中，我提出了一种概念性小说的方法 通过关注“排除”染色体来解决AD病理学的性别差异。与 在AD遗传学领域的专家同事，我将采用最新技术来检查基因组， 不活跃X的转录组和表观遗传影响逃脱了基因作为体内性别差异的驱动力 B-淀粉样蛋白和Tau的神经影像标记。这项研究的范围将是无与伦比的，因为我将利用我的 神经影像学，数据协调和统计的技能，结合了三个大型，深度型的人群 具有B-淀粉样蛋白和Tau正电子发射断层扫描神经影像学以及整个基因组的样品 转录组测序（n = 900）和血液中的促炎标记：哈佛大学衰老大脑研究 （HAB），非对称阿尔茨海默氏症（A4）研究和纵向评估的抗淀粉样蛋白治疗 淀粉样蛋白风险和神经退行性研究（学习）研究。我还将在宗教命令中验证我的发现 研究，记忆和老化项目（ROS/MAP）和阿尔茨海默氏病神经影像学计划（ADNI）。 阐明针对AD风险的性别特异性机制对识别药物靶标有深远的影响， 但也可以更好地预测临床试验中男性和女性药物反应结果。