Modeling Alzheimer's Disease in Hispanic Latino populations using human cortical organoids

使用人类皮质类器官模拟西班牙裔拉丁裔人群的阿尔茨海默病

• 批准号: 10680168
• 负责人: Karina K Meyer-Acosta
• 金额: $ 3.89万
• 依托单位: UNIVERSITY OF TEXAS SAN ANTONIO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680168
• 关键词: 3-Dimensional; Abeta synthesis; Address; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Biological Assay; Biological Models; Biology; Brain; Cell Death; Cells; Central America; Cerebrum; Cessation of life; Characteristics; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Disease; Disease model; Dorsal; Enzyme-Linked Immunosorbent Assay; Ethnic Origin; Ethnic Population; Fellowship; Gene Expression; Genes; Genetic; Genetic Risk; Genetic Transcription; Genetic Variation; Genetic study; Genome; Genotype; Geography; Growth; Heritability; Hispanic; Hispanic ancestry; Human; Immunohistochemistry; Impaired cognition; Impairment; In Vitro; Individual; Latino Population; Learning; Measures; Mediating; Methods; Mexican; Mexican Americans; Molecular; Neuroglia; Neurons; Not Hispanic or Latino; Organoids; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Phenotype; Physiological; Population; Population Heterogeneity; Proliferating; Proteins; Risk; Role; Scientist; South American; Support Groups; Testing; Training; Variant; Western Blotting; apolipoprotein E-3; apolipoprotein E-4; cell type; differential expression; disease phenotype; disorder risk; ethnic diversity; excitatory neuron; experimental study; genetic manipulation; genetic risk factor; genome wide association study; health disparity; high risk; induced pluripotent stem cell; induced pluripotent stem cell technology; inhibitory neuron; insight; multi-ethnic; new therapeutic target; novel; protective effect; protein expression; risk variant; skills; stem; stem cell technology; tau-1; therapeutic target; transcriptome sequencing

Project Summary/Abstract Hispanic Latinos (HLs) have the highest risk of developing Alzheimer’s disease (AD) and related dementias, the highest proportion of any ethnic group in the US. In genome-wide association studies (GWAS) conducted mostly in non-Hispanic white (NHW) individuals, Apolipoprotein E4 (APOE4) was established as the leading AD genetic risk factor, increasing risk 3-12 fold compared to the non-risk allele, APOE3. In HLs however, there is discordant evidence about the association of APOE4 with AD which is at least partially attributed to the genetic diversity of HLs stemming from widespread geographic origins. GWAS in large HL populations identified ancestry native to Central America, the primary ancestry of Hispanic Mexican Americans (HMA), have little to no AD association with APOE4. Studies further suggest that inheritance of APOE4 allele from native ancestor may not increase AD risk to the same extent as that observed in NHW. It is postulated that genetic variation, possibly regulatory, either local to APOE allele, or across the genome, modifies APOE4 biology. Recently, genetic variation local to APOE was shown to dominantly influence gene transcription and APOE expression independent of APOE genotype. Gaining insight on the molecular basis by which HMA background modifies APOE4 biology would identify protective mechanisms against AD. My central hypothesis is that APOE4 will be associated with AD-related phenotypes in cortical organoids with NHW ancestry, but not with HMA ancestry, or to a lesser extent. Since AD develops decades before cognitive decline and ethnic variation is human-specific, I will test my hypothesis in 3D cortical organoids. I will generate excitatory neuron-enriched human cortical organoids (hCO), and inhibitory neuron-enriched human subpallial organoids (hSO) to explore neuron subtype-specific differences in AD-related phenotypes. To investigate cellular phenotypes mediated by APOE4 with respect to genetic background, I will 1) characterize the effect of APOE4 on AD-related cellular phenotypes within NHW background, and 2) determine the effect of HMA background on APOE4 mediated phenotypes and gene transcription. My preliminary data suggests that the APOE4 allele reduces growth and upregulates APOE expression in both hCO and hSO compared to organoids carrying the non-risk allele, APOE3. Aim 1 will explore the cellular basis contributing to size (differentiation, maturation, and cell death) and characterize AD-related pathology by immunostaining and protein expression assays. To control for patient background and assess the specific effects of APOE4 genotype and genetic background, I will gene-edit APOE3 to APOE4 in iPSCs with NHW and HMA backgrounds. In Aim 2, I will determine the phenotypic and transcriptional changes associated with HMA background on APOE4- mediated AD-related phenotypes. Under this fellowship, I will expand my molecular toolkit and in vitro disease modeling and hone my skills as a molecular neuroscientist. I will also strengthen my analytical skills and learn new methods to probe gene expression by training under my sponsor and a supporting group of scientists.

项目摘要/摘要 西班牙裔拉丁裔（HLS）的风险最高，患阿尔茨海默氏病（AD）和相关痴呆症， 美国任何种族的最高比例。在全基因组关联研究（GWAS）中主要进行 在非西班牙裔白人（NHW）个体中，Apolipopprotein E4（APOE4）被确定为领先的AD通用通用。 风险因素，与非风险等位基因APOE3相比，风险增加3-12倍。但是，在HLS中，有不和谐的 关于APOE4与AD的关联的证据，至少部分归因于遗传多样性 HLS源于广泛的地理起源。大量HL种群中的GWA被确定为原生的祖先 中美洲是西班牙裔墨西哥裔美国人（HMA）的主要血统，几乎没有广告协会 与apoe4。研究进一步表明，来自本地祖先的ApoE4等位基因的遗传可能不会增加AD 与NHW中观察到的相同程度的风险。据推测，遗传变异（可能的调节） 局部对ApoE等位基因，或跨基因组修饰APOE4生物学。最近，遗传变异与APOE局部 显示出独立于APOE基因型的主要影响基因转录和APOE表达。 获得HMA背景修饰符APOE4生物学识别的分子基础的见解 保护AD的保护机制。我的中心假设是APOE4将与广告相关 具有NHW血统的皮质器官的表型，但没有HMA祖先或较小程度。自广告以来 在认知能力下降和种族差异之前发展几十年是人类特异性的，我将在3D中检验我的假设 皮质器官。我将产生富含神经元的兴奋性人体皮质器官（HCO）和抑制性 富含神经元的人类亚paralli器官（HSO），以探索与AD相关的神经元亚型特异性差异 表型。为了研究由APOE4介导的遗传背景介导的细胞表型，我将 1）表征APOE4对NHW背景中与AD相关的细胞表型的影响，2） 确定HMA背景对APOE4介导的表型和基因转录的影响。我的初步 数据表明，APOE4等位基因降低了HCO和HSO中的APOE表达 与携带非风险等位基因的类器官相比，APOE3。 AIM 1将探索促进的细胞基础 大小（分化，成熟和细胞死亡），并通过免疫染色和 蛋白质表达测定。为了控制患者背景和评估APOE4基因型的特定影响 和遗传背景，我将在具有NHW和HMA背景的IPSC中的apoE4基因APOE3。目标 2，我将确定与APOE4-的HMA背景相关的表型和转录变化 介导的与广告相关的表型。在此奖学金下，我将扩展我的分子工具包和体外疾病 建模并尊重我作为分子神经科学家的技能。我还将增强我的分析能力并学习 通过我的赞助商和支持科学家的支持小组培训探测基因表达的新方法。