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Establishment of Somatic Cell Nuclear Transfer as a Universal Platform for Cloning Marmosets

体细胞核移植作为克隆狨猴通用平台的建立

基本信息

批准号：
10682479
负责人：
Jung Eun Park
金额：
$ 19.88万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
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：
2022-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10682479
关键词：
Address Anatomy Aneuploidy Animals Antimitotic Agents Biomedical Research Birth Brain CADASIL CRISPR/Cas technology Callithrix Callithrix jacchus jacchus Cell Nucleus Cell fusion Characteristics Chemicals Chromosomes Chronic Cloning Cognitive Combined Modality Therapy Communities Complex Crossbreeding Cytoplasm Cytosine DNA DNA Methylation DNA methyltransferase inhibition DNMT3B gene DNMT3a Deacetylase Development Domestic Animals Early Onset Alzheimer Disease Embryo Embryo Cloning Embryo Transfer Embryonic Development Epigenetic Process Female Funding Gene Expression Gene Expression Profile Gene Transfer Techniques Generations Genes Genetic Genetic Engineering Genetic study Goals Histone Acetylation Histones Human In Vitro Individual Infant Measures Mechanics Messenger RNA Metabolic Metaphase Methods Methyltransferase Microvascular Dysfunction Modeling Mosaicism Mus Mutation NOTCH3 gene Neurosciences Research Nuclear Oocytes Ooplasm Phenotype Phylogenetic Analysis Physiological Pregnancy Procedures Process Protocols documentation RNA Research Research Support Social Behavior Somatic Cell Stains System Techniques Technology Term Birth Testing Totipotent Transgenes Transgenic Organisms Translational Research Ultraviolet Rays United States National Institutes of Health Variant Work assistive reproductive technique blastocyst calcium indicator efficacy evaluation epigenome experience genome editing histone demethylase human disease human model immune function improved inhibitor interest mosaic nervous system disorder neuropsychiatric disorder nonhuman primate novel nuclease presenilin-1 preservation prevent reproductive somatic cell nuclear transfer tool translational neuroscience

项目摘要

PROJECT SUMMARY/ABSTRACT The common marmoset (Callithrix jacchus) is a New World non-human primate (NHP) with several practical advantages in biomedical research. Due to their phylogenetic proximity, marmosets are a genetically diverse NHP species with similar physiological, metabolic, and immunological functions as humans. Marmosets retain the typical anatomical and functional organization of the human brain. Marmosets have complex cognitive and social behavior. The above characteristics place marmosets as an ideal NHP model to bridge the gap between mice and humans for both basic and translational neuroscience. Marmosets reach sexual maturity at circa 18 months and give birth to multiple infants twice a year. Their short gestation period and compatibility with gene editing techniques make marmosets ideally poised to become the NHP model of choice in studying the genetic causes of neurological and neuropsychiatric disorders and understanding brain function. We have successfully generated transgenic marmosets expressing genetically encoded calcium indicators and genetically engineered marmosets with NOTCH3 mutations that cause the small vessel disease CADASIL. We have also made marmosets harboring PSEN1 mutations that cause early-onset Alzheimer’s disease. Our gene-edited marmosets will enable us to investigate the genetic causes of chronic neurological disorders. However, two main issues hinder the broader availability of genetically engineered marmosets. First, lentiviral-based approaches suffer from an uncontrollable integration of transgene with variation in copy number, and nuclease-based gene editing produces embryos with mosaic editing, leading to unpredictable gene expression patterns and variable phenotype. Second, and most importantly, there are no efficient ways to propagate an individual showing the interest phenotype. This proposal addresses these shortcomings by developing and optimizing somatic cell nuclear transfer (SCNT) as a universal platform for cloning marmosets. We want to build on our vast experience generating genetically modified marmosets to (1) develop and optimize the enucleation procedure in marmoset somatic cell nuclear transfer and (2) develop and optimize approaches enabling technologies for efficient epigenetic reprogramming during somatic cell nuclear transfer in the marmoset. These results will establish optimized marmoset SCNT protocols and unravel a novel enabling universal platform to generate a sizeable number of cloned marmosets expressing any phenotype of interest. This platform will significantly facilitate the propagation and sharing of marmoset models for neuroscience and translational research supported by multiple NIH ICs.

项目总结/文摘