Generation and analysis of new mouse models to determine novel therapeutic targets for Down syndrome-associated cognitive deficits

生成并分析新的小鼠模型以确定唐氏综合症相关认知缺陷的新治疗靶点

基本信息

批准号：
10704099
负责人：
Eugene Yu
金额：
$ 46.07万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
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：
2022-09-13 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10704099
关键词：
3-Dimensional Affect Animals Architecture Candidate Disease Gene Cells Cerebral cortex Characteristics Chromosomal Rearrangement Chromosome 16 Chromosome 21 Chromosome abnormality Chromosomes Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Cognitive deficits Consensus Data Development Developmental Delay Disorders Dissection Down Syndrome Edward&apos s syndrome Engineering Exhibits Gene Dosage Gene Expression Generations Genes Genetic Genome Genome engineering Genomic Segment Genotype Goals Human Human Chromosomes IFNAR1 gene Incidence Individual Intellectual functioning disability Interferon Receptor Investments Live Birth Maps Mediating Medical Modeling Molecular Mus Mutant Strains Mice Nervous System Newborn Infant Nuclear Orthologous Gene Outcome Patau&apos s syndrome Penetrance Persons Phenotype Play Process Quality of life Reporting Research Role SYNJ1 gene Technology Testing Therapeutic Trisomy United States clinical phenotype cognitive ability cognitive enhancement cognitive function dosage effective therapy gene discovery genetic analysis improved inhibitor innovation mouse Ts65Dn mouse model mutant new therapeutic target novel segregation success therapeutic target

项目摘要

ABSTRACT The presence of an extra copy of human chromosome 21 (trisomy 21) is associated with Down syndrome (DS), and this is the most common live-born chromosomal alteration in humans. In the United States, DS has an incidence rate of approximately 1 in 691 newborns, and individuals with DS exhibit many clinical phenotypes; nervous system involvement is among the most burdensome. Today, human trisomy 21 remains a leading genetic cause of developmental delays and intellectual disabilities with near universal penetrance. Effective treatments for such clinical manifestations would be transformative because these treatments could profoundly improve the quality of life for individuals with DS. Based on the prevailing hypothesis that particular phenotypes of DS are affected by the dosage increase of specific genes on human chromosome 21 (Hsa21), triplications of particular genomic segments, i.e., human segmental trisomies, have been studied in detail to establish genotype–phenotype relationships with the ultimate goal of identifying dosage sensitive causative genes that can serve as therapeutic targets. However, such efforts have been severely hampered by the lack of an adequate number of informative segmental trisomy cases. Fortunately, amore fruitful alternative based on the evolutionary conservation between humans and mice has also been pursued, and this approach has allowed the genetic dissection efforts to advance much more rapidly. For example, analyses of the DYRK1A gene ortholog in mice demonstrated that this gene is a causative determinant for DS-associated developmental cognitive deficits; subsequently, these results served as the basis for the only successful clinical trials involving developmental cognitive deficits and orthologous Hsa21 genes. To further the genetic dissection efforts, we have developed a large number of mouse mutants carrying different chromosomal rearrangements in Hsa21 orthologous regions. In Aim 1 of this application, we will utilize these mouse mutants and develop new mutants by using CRISPR - mediated genome engineering to enhance our efforts to identify novel dosage sensitive causative genes underlying developmental cognitive deficits in DS, whose human orthologs can serve as therapeutic targets along with the DYRK1A gene. Besides acting through a gene dosage increase, human trisomy 21 may have other ways of influencing phenotypes, such as by altering the nuclear architecture and thus gene expression. In Aim 2 of this application, we will test this second hypothesis by using mouse models. We believe the success of our proposed project will have a transformative impact on research on DS in general and on DS-associated developmental cognitive deficits in particular.

抽象的人类染色体21（三体疾病）的额外副本的存在与唐氏综合症（DS）有关这是人类中最常见的现场直播染色体改变。在美国，DS有一个在691名新生儿中约有1个，患有DS的人的发病率大约显示出许多临床表型。神经系统的参与是最繁重的。今天，人类三体第21人仍然是领先的发育延迟和智力残疾的遗传原因几乎普遍渗透。有效的这种临床表现的治疗方法将是变革性的，因为这些治疗可以深刻地改善DS患者的生活质量。基于特定表型的普遍假设 DS的特定基因在人类染色体21（HSA21）上的剂量增加，一式三份特定的基因组段，即人类节段trisomies，已经详细研究了基因型 - 表型与识别剂量敏感灾难性基因的最终目标的关系可以用作治疗靶标。但是，由于缺乏足够的足够，这种努力受到了严重阻碍内容丰富的节段三体病例的数量。幸运的是，基于进化的富有成果的替代品人类和小鼠之间的保护也已被追求，这种方法允许通用解剖努力以更快的速度进步。例如，小鼠DYRK1A基因直系同源物的分析证明该基因是与DS相关开发者认知缺陷的关键决定剂。随后，这些结果是唯一成功临床试验的基础认知缺陷和直系同源的HSA21基因。为了进一步遗传剖析，我们开发了一个在HSA21直系同源区域中携带不同染色体重排的大量小鼠突变体。在本应用程序的AIM 1中，我们将利用这些小鼠突变体并使用CRISPR开发新的突变体 - 介导的基因组工程，以增强我们识别新剂量敏感灾难性基因的努力 DS中发展的认知缺陷的潜在基础，其人类直系同源物可以作为治疗靶标与dyrk1a基因一起。除了通过基因剂量升高作用外，人类三体三体可能具有影响表型的其他方法，例如改变核结构，从而改变基因表达。该应用程序的目标2，我们将使用鼠标模型检验第二个假设。我们相信我们提出的项目将对一般对DS的研究和DS相关的研究产生变革性的影响尤其是开发人员的认知缺陷。