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.

项目总结/文摘