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Regulation of the DYRK1A kinase by the Down Syndrome Cell Adhesion Molecule DSCAM

唐氏综合症细胞粘附分子 DSCAM 对 DYRK1A 激酶的调节

基本信息

批准号：
10573072
负责人：
PETER Gerard FUERST
金额：
$ 15万
依托单位：
UNIVERSITY OF IDAHO
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：
2022-09-08 至 2023-02-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10573072
关键词：
Address Affect Aneuploidy Area Axon Biochemical Biological Assay Blindness Brain Brain region Cell Adhesion Molecules Cell Death Cell Nucleus Cell Surface Receptors Cell surface Cellular biology Cerebellum Chromosome 16 Chromosome 21 Clinical Cues Cytoplasmic Tail Data Defect Dendrites Development Disease Down Syndrome Down Syndrome Cell Adhesion Molecule Environment Event Eye Foundations Future Gene Duplication Gene Expression Genes Genetic Genetic study Goals Hippocampus (Brain)Human Chromosomes Idaho In Vitro Intervention Knowledge Link Mediating Modeling Molecular Morphology Mosaicism Mus Mutation Nervous system structure Neurites Neurons Neurophysiology - biologic function Nuclear Nuclear Translocation Organ Outcome Pathology Persons Phenocopy Phenotype Phosphotransferases Pilot Projects Play Population Proteins Publications Reagent Regulation Reporting Research Research Proposals Retina Role Schizophrenia Scientist Signal Pathway Signal Transduction Signaling Molecule Signs and Symptoms Specificity Surface Syndrome System Testing Time Tissues Tyrosine Phosphorylation Universities Work autism spectrum disorder base cell type dosage experience experimental study gain of function human disease loss of function mouse Ts65Dn mouse model neurodevelopment novel overexpression postnatal prevent receptor relating to nervous system response retinal neuron

项目摘要

ABSTRACT: Candidate and Environment: The Fuerst Lab will conduct genetic, molecular and morphological experiments related to the Aims of this proposal at the University of Idaho. The Fuerst lab team has extensive expertise centered on the cell biology and genetics of neural development. Fuerst identified Dscams as the first molecules that regulate mosaic organization of neurons and developed many of the genetic reagents for use in these experiments. Here we will build on our foundation of experience studying Dscam genes to probe the function of downstream signaling networks in neural development. Research Proposal: Developing neurons utilize a range of molecular cues to organize into neural tissues and organs. We and others have previously reported that Down syndrome cell adhesion molecule (Dscam) genes are required for normal development of neural tissues. How Dscam genes mediate a wide range of cellular responses even within a single cell type is an active area of research. In our preliminary studies we found that overexpression of Dyrk1a, whose product interacts biochemically with DSCAM, phenocopies Dscam loss of function. Further we report a redistribution of cellular DYRK1A protein in the Dscam loss of function retina and brain. Based on these observations and the genes’ known antagonistic roles in either promoting or inhibiting developmental cell death, we hypothesize that DSCAM interactions on the cell surface antagonize DYRK1A activity by controlling its subcellular localization. We test this hypothesis in two specific Aims. Aim 1: Pilot genetic studies indicate that either decreasing Dscam dosage or increasing Dyrk1a dosage results in mistargeting of retinal neuron neurites. A similar increase in Dyrk1a expression in the Ts65Dn trisomic mouse models results in a wild type targeting phenotype, however, suggesting a factor or factors in the Down syndrome critical region (DSCR) are compensating for Dyrk1a overexpression. First, we will test if increasing Dyrk1a expression in the Ts65Dn mouse model above the expression of other DSCR genes is sufficient to restore Dyrk1a overexpression neurite targeting defects (Aim 1A). Second, we will test if reducing Dscam expression in Ts65Dn mice to wild type levels restores the Dyrk1a overexpression phenotype (Aim 1B). Aim 2: We will extend our pilot study generated in retina into the brain at large. We will test if DYRK1A localization is developmentally dynamic in the brain (Aim 2A), if DSCAM regulates DYRK1A localization in the brain (Aim 2B) and if Dscam expression is sufficient to modify DYRK1A accumulation or localization in vitro (Aim 2C). Long-term goals: Our long-term goal is to understand how events at the cell surface are transduced to generate different cellular responses. This R03 will facilitate completion and publication of a pilot study, the results of which will inform experiments to understand how regulation of DYRK1A localization impacts its function in development and disease. Significance: Understanding why mutation or overexpression of genes involved in neural development can present with a variety of signs and symptoms in people will require us to also understand the functions of the affected genes with the long-term goal of developing clinical interventions. Here we explore the interaction between two interacting genes in the Down Syndrome critical region, relevant to studies and treatments focusing on either single gene. Understanding the downstream signaling pathways utilized by surface receptors will be essential to help scientists and clinicians pinpoint strategies to treat human diseases.

摘要：候选物与环境：富尔斯特实验室将开展遗传、分子和形态学研究