A brain multi-omic approach to identify key molecular drivers of neuropsychiatric symptoms in Alzheimer's dementia

大脑多组学方法识别阿尔茨海默氏痴呆症神经精神症状的关键分子驱动因素

基本信息

批准号：
10366260
负责人：
Aliza Pham Wingo
金额：
$ 80.86万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2027-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10366260
关键词：
Accounting Address Affect Agitation Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Anxiety Autopsy Biological Process Bipolar Disorder Brain Caregiver Burden Caregivers Characteristics Data Delusions Dementia Disease Progression Disinhibition Drug Targeting Environment Future Genes Genetic Genetic Risk Genets Genotype Hallucinations Heritability Human Individual Institutionalization Knowledge Major Depressive Disorder Measures Mediator of activation protein Medical Mental Depression Mental disorders Modeling Molecular Participant Pathogenesis Pathway Analysis Pathway interactions Pharmaceutical Preparations Phenotype Plasma Prefrontal Cortex Proteins Proteome Proteomics Public Health Publishing Role Schizophrenia Signal Transduction Sleep disturbances Testing Therapeutic Studies Transcript Translating United States Variant Work brain tissue causal variant comorbidity differential expression disabling symptom effective therapy experience functional disability genetic variant genome wide association study genome-wide insight mild cognitive impairment mortality multiple omics neuropsychiatric symptom new therapeutic target novel pleiotropism potential biomarker protein expression risk variant side effect therapeutic target transcriptome transcriptomics

项目摘要

Approximately 65% of individuals with mild cognitive impairment (MCI), Alzheimer's disease (AD), or AD related dementias (ADRD) experience neuropsychiatric symptoms (NPS). These debilitating symptoms include depression, anxiety, apathy, delusions, hallucinations, agitation, sleep disturbances and are associated with faster disease progression, greater functional impairment, higher caregiver burden, and earlier institutionalization. Current treatments for NPS in MCI/dementia have limited efficacy but high rates of adverse side effects, including higher mortality. Therefore, safe and effective treatments for NPS are urgently needed. However, we have limited insights into molecular mechanisms of NPS in MCI/dementia to nominate therapeutic targets. To address this knowledge gap, we aim to elucidate the genetic and molecular mechanisms underlying NPS in MCI/dementia using two complementary but independent approaches. In the first approach, we will leverage the substantial genetic basis of NPS (heritability of ~61%) to identify novel genes involved in NPS. First, we will perform genome-wide association studies (GWAS) of NPS in ~32,000 individuals with MCI/AD/ADRD from across the United States. We will perform a GWAS of each NPS domain as well as a multivariate GWAS of all NPS collectively. Results of each GWAS will be integrated with reference human brain transcriptomic and proteomic profiles to identify individual brain transcripts and proteins that are consistent with being causal in NPS. We have applied these integrative approaches to AD and identified 11 genes that regulate their brain protein abundances to predispose to AD (Wingo et al. 2021, Nat Genet). Unlike GWAS results, these findings point to specific brain proteins that are consistent with a causal role in AD. Importantly, this approach does not solely depend on genome-wide significant signals, and the causal inference of this integrative strategy has been experimentally tested and found to be robust. Thus, we expect that findings from this approach will provide novel insights into the pathogenesis of NPS. Our second approach aims to identify brain transcripts, proteins, and co-expression networks associated with NPS. We will perform transcriptomic and proteomic sequencing of post-mortem brain tissues from 400 individuals with MCI/AD and longitudinal NPS assessment, as existing brain omics data do not have robust NPS measures. Then we will examine NPS domains individually as well as collectively in our differential expression and network analyses. We anticipate that molecular alterations at the brain transcript and protein levels identified with this approach will provide insights into NPS pathogenesis and progression. Studying both transcripts and proteins would provide complementary information and a more complete molecular picture. We view understanding proteins as particularly important since they are the vast majority of drug targets. The proposed project will likely lead to new insights into molecular mechanisms and novel therapeutic targets for NPS and thereby have an important and sustained impact on public health.

大约 65% 的人患有轻度认知障碍 (MCI)、阿尔茨海默病 (AD) 或 AD 相关痴呆 (ADRD) 会出现神经精神症状 (NPS)。这些使人衰弱的症状包括抑郁、焦虑、冷漠、妄想、幻觉、烦躁、睡眠障碍，并且与疾病进展更快、功能损伤更大、护理人员负担更高以及更早制度化。目前针对 MCI/痴呆症的 NPS 治疗效果有限，但不良反应发生率很高副作用，包括更高的死亡率。因此，迫切需要安全有效的NPS治疗方法。然而，我们对 MCI/痴呆中 NPS 的分子机制了解有限，无法提名治疗目标。为了解决这一知识差距，我们的目标是阐明遗传和分子使用两种互补但独立的方法来研究 MCI/痴呆症中 NPS 的机制。在第一种方法中，我们将利用 NPS 的实质性遗传基础（约 61% 的遗传力）来识别与 NPS 相关的新基因。首先，我们将进行NPS的全基因组关联研究（GWAS）来自美国各地的约 32,000 名 MCI/AD/ADRD 患者。我们将对每个项目进行 GWAS NPS 域以及所有 NPS 的多元 GWAS 的统称。每个 GWAS 的结果将被整合参考人脑转录组和蛋白质组图谱来识别个体大脑转录本和与 NPS 中的因果关系一致的蛋白质。我们已将这些综合方法应用于AD 并确定了 11 个调节大脑蛋白质丰度以诱发 AD 的基因（Wingo 等人，2021 年，纳特·吉内特）。与 GWAS 结果不同，这些发现指出特定的大脑蛋白质与 AD 中的因果作用。重要的是，这种方法不仅仅依赖于全基因组的重要信号，而且这种综合策略的因果推理已经过实验测试并被发现是稳健的。因此，我们期望这种方法的发现将为 NPS 的发病机制提供新的见解。我们的第二种方法旨在识别大脑转录本、蛋白质和共表达网络与 NPS 相关。我们将对死后脑组织进行转录组和蛋白质组测序来自 400 名患有 MCI/AD 和纵向 NPS 评估的个体，因为现有的脑组学数据没有稳健的 NPS 措施。然后，我们将在我们的差异中单独和集体检查 NPS 域表达和网络分析。我们预计大脑转录本和蛋白质的分子改变通过这种方法确定的水平将为 NPS 发病机制和进展提供见解。两者都在学习转录本和蛋白质将提供补充信息和更完整的分子图片。我们认为了解蛋白质特别重要，因为它们是绝大多数药物靶点。拟议的项目可能会带来对分子机制和新疗法的新见解 NPS 目标，从而对公众健康产生重要且持续的影响。