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Advancing brain health research through male germline editing in marmosets

通过狨猴雄性种系编辑推进大脑健康研究

基本信息

批准号：
10459513
负责人：
Brian Peter Hermann
金额：
$ 222.94万
依托单位：
UNIVERSITY OF TEXAS SAN ANTONIO
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-01 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10459513
关键词：
3-Dimensional ATAC-seq Address Adult Affect Alleles Allogenic Anatomy Animals Area Behavioral Assay Biological Models Brain Brain Diseases Breeding CRISPR/Cas technology Callithrix Callithrix jacchus jacchus Cell Transplantation Cells ChIP-seq Chimerism Chromatin Clinic Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Communities Complex DNA Methylation Defect Derivation procedure Development Disease Embryo Enterobacteria phage P1 Cre recombinase Epigenetic Process Epilepsy Failure Fostering Gene Expression Gene Transfer Techniques Genes Genetic Genome Genomics Germ Germ Cells Germ Lines Goals Health Histology Homeobox Homeobox Genes Human In Vitro Injections Intellectual functioning disability Interneurons Knock-in Knowledge Laboratories Link Longevity Magnetic Resonance Imaging Mediating Methodology Methods Modeling Modification Mus Mutation Neuroanatomy Neurobiology Neurodegenerative Disorders Neurologic Neurons Newborn Infant Normalcy Operative Surgical Procedures Organoids Pathway interactions Pharmaceutical Preparations Pluripotent Stem Cells Population Pregnancy Primates Production Protocols documentation Publishing Reporter Research Research Personnel Rodent Rodent Model Seeds Source Spermatocytes Spermatogenesis Study models System Testis Therapeutic Tissues Transgenes Transgenic Organisms Translating Translations Transplantation United States National Institutes of Health Validation Xenograft procedure base bisulfite sequencing brain health brain research cell type clinical predictors clinically relevant cognitive process design disability epigenomics experience fetal genome editing histone modification human model in vivo induced pluripotent stem cell infancy innovation innovative neurotechnologies interest lissencephaly male malformation migration mutant nervous system disorder neurogenetics neuron development neuropsychiatric disorder neuropsychiatry non-invasive imaging nonhuman primate novel novel strategies novel therapeutics offspring polyalanine postnatal reconstitution relating to nervous system single-cell RNA sequencing skills sperm cell success therapeutically effective therapy design/development tool transcriptome sequencing transmission process whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT Neuropsychiatric disorders represent a leading cause of disability, affecting nearly 19% of the US population. Only 9% of neuropsychiatric drugs entering clinical trials reach the market, which is one of the lowest success rates across all therapeutic areas. Fundamental differences between the neurobiology of rodents and humans have been proposed to account for translational failures in development of effective therapeutic strategies to mitigate neurological or neurodegenerative diseases or disorders. Rodent behavioral assays are also variably effective in predicting clinically effective neuropsychiatric drugs. Nonhuman primates (NHPs) are recognized as a valuable, clinically relevant alternative to span the gap between rodents and humans in the development of therapies designed to advance brain health. Among NHPs, the common marmoset [Callithrix jacchus (cj)] affords a highly tractable option because of its small size, short lifespan, production of multiple offspring/year and accurate recapitulation of human neuroanatomy. However, the ultimate utility of the marmoset model remains in its infancy due to the paucity of efficient tools to facilitate studies requiring genetic modification, especially those needed to recapitulate complex aspects of brain health. To address this urgent need, we propose an innovative, more efficient approach to achieve gene editing and transgenesis in marmosets based on the novel use of highly manipulable induced pluripotent stem cells (iPSCs) that can be differentiated to form male germ cells that can ultimately be used to produce transgenic offspring carrying precisely edited alleles of genes relevant to brain health and disease. Specifically, we will combine 1) close proximity to one of two NIH-designated Marmoset Breeding Colonies, maintained at the Southwest National Primate Research Center, 2) experience with NHP pluripotent stem cells, iPSC derivation, and CRISPR/Cas9 editing, 3) a novel strategy to produce transplantable male germ cells from edited cjiPSCs, 4) documented expertise transplanting NHP germ cells into testes to produce sperm, 5) published experience in the use of cutting-edge single-cell genomics and multiparametric integrative epigenomics to assess normality of any cell type, and 6) leading expertise in brain health and disease in general and the neurogenetics of epilepsy in particular. In Aim 1, we will use CRISPR editing to generate mutant ARX alleles and reporter transgenes in cjiPSCs. In Aim 2, we will optimize derivation and transplantation of male cjiPSC-derived germ cells into recipient testes and grafts to foster development of transgenic sperm. In Aim 3, we will assess the impact of ARX mutations on marmoset cortical neuron development and migration. Together, these aims are designed to advance the utility of the marmoset model for brain research based on CRISPR/Cas9 editing of cjiPSCs, male germline-mediated transgenesis, development of cjiPSC-derived brain organoids, and specific knowledge of the neurological impact of ARX mutations.

项目总结/文摘