Hedgehog Treatment of Down Syndrome: Establishing Mechanisms

唐氏综合症的刺猬疗法：建立机制

基本信息

批准号：
8808144
负责人：
Roger H Reeves
金额：
$ 24.3万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8808144
关键词：
Adrenal hormone preparation Adult Adverse effects Affect Age Age-Months Agonist Anatomy Antibiotics Area Attenuated Behavior Biological Assay Birth Brain Brain Part Brain region Cell Count Cell Proliferation Cells Cerebellum Child Childhood Chromosomes, Human, Pair 21 Clinic Cognitive Complementary DNA Congenital cerebellar hypoplasia Country Cytoplasmic Granules DNA Data Development Dose Down Syndrome Down-Regulation Doxycycline Drug Delivery Systems Embryonic Development Emotional Epidemiology Erinaceidae Evaluation Exposure to Family Gene Expression Genes Genetic Growth Factor Hippocampus (Brain)Human Human Cell Line Human Chromosomes Injection of therapeutic agent Intellectual functioning disability Journals Laboratories Learning Life Light Link Luciferases Malignant Neoplasms Malignant neoplasm of brain Maps Mediating Medical Memory Methods Mitotic Morphology Mothers Motion Mus Mutation Neonatal Neural Crest Cell Neurons Oncogenic Orthologous Gene Performance Persons Pharmacology Physiology Play Population Problem Solving Process Production Prosencephalon Purkinje Cells Recovery Resistance Role Series Signal Transduction Site Societies Sonic Hedgehog Pathway Structure Synaptic plasticity Syndrome System Testing Tetanus Helper Peptide Therapeutic Thyroid Hormones Time Translating Trisomy Validation Water biological systems cDNA Library cell transformation combinatorial cost dentate gyrus disability expression cloning gene function granule cell human SMO protein improved in vivo medulloblastoma mouse Ts65Dn mouse model neonate neuro-oncology overexpression postnatal programs promoter public health relevance pup research study response restraint screening small molecule smoothened signaling pathway young adult

项目摘要

DESCRIPTION (provided by applicant): Down syndrome (DS), caused by trisomy for human chromosome 21 (Hsa21), is the most common genetically defined cause of intellectual disability. Structural abnormalities that are thought to contribute to learning problems are seen in the cerebellum and hippocampus of people with the condition. Treatments to correct these parts of the brain would tangibly improve the lives of children and young adults with DS and would allow them to better integrate into society. We recently showed that a single injection on the day of birth with the Sonic Hedgehog (Shh) agonist, SAG 1.1, permanently normalizes the size and gross anatomy of the cerebellum, leads to better adult spatial problem solving, and restores electrophysiological correlates of learning in the CA1-hippocampal subfield of the Ts65Dn mouse model of DS. A number of questions remain before this finding can be translated to therapy for people. Whether improvements in hippocampal behavior & physiology occur through Shh-induced normalization of cerebellar structure or via direct stimulation with Shh is not known. Another restraint on advancing Shh treatments to the clinic is the very wide range of effects of this potent growth factor, making systemic application in people problematic. A more confined method of drug delivery might limit side effects. Another approach would be to understand which Hsa21 genes act to downregulate the Shh pathway response in cerebellum, which might suggest more "druggable" targets. The experiments proposed here will first screen Shh responses with an Hsa21 Gene Expression clone-set of 169 cDNAs, 149 of which are highly conserved between human and mouse and twenty that are human specific. Genes that significantly decrease Shh pathway activation in the LIGHT2 assay will be evaluated in additional Shh-sensitive assays to assure that they generalize across different biological systems (Specific Aim 1). Next, we will determine how region-specific expression of Shh in the Ts65Dn brain affects hippocampal function. Using a conditional "temporal-spatial" genetics approach that will allow us to increase Shh expression at birth for a 24h period selectively within the Purkinje cells of the cerebellum, or within the hippocampus, we will determine whether cerebellar Shh expression is necessary and/or sufficient to correct the behavior & physiology of adult Ts65Dn mice in hippocampal tests or whether Shh actions in additional parts of the brain are required (Specific Aim 2).

描述（由适用提供）：唐氏综合症（DS）是由人类染色体的三体染色体（HSA21）引起的，是智障最常见的遗传定义原因。被认为有助于学习问题的结构异常在有这种疾病的人的小脑和海马中可以看到。纠正大脑这些部分的治疗方法将有明显地改善DS儿童和年轻人的生活，并可以使他们更好地融入社会。我们最近表明，在出生当天的单一注射刺激器（SHH）激动剂（SAG 1.1）永久归一化，使小脑的大小和严重解剖结构导致了更好的成人空间问题解决，并恢复了CA1-HAIMPAMPAMPAL MEABLIEVE中的电动生理学相关性，这是TS665D DS 65D ds d.Ds d.Ds d.Ds d.Ds d.ds d.ds d.ds d.ds d.ds d.ds d d d d d d d d d d d d d d d d d d d d d d d.在这一发现之前，仍有许多问题可以将其转化为人们的治疗。无论是通过SHH引起的小脑结构的归一化还是通过用SHH直接刺激进行海马行为和生理的改善，尚不清楚。将SHH治疗推进诊所的另一个限制是该潜在生长因子的广泛影响，使系统的应用有问题。药物输送的一种更牢固的方法可能会限制副作用。另一种方法是了解哪种HSA21基因在小脑中下调了SHH途径反应，这可能暗示了更多“可药”靶标。此处提出的实验将首先使用169个cDNA的HSA21基因表达克隆式筛选SHH响应，其中149个在人和小鼠之间高度保守，而二十个是人类特异性的。将在其他SHH敏感的刺客中评估Light2测定法中SHH途径激活的基因，以确保它们跨越不同的生物系统（特定目标1）。接下来，我们将确定TS65DN大脑中SHH的特异性表达如何影响海马功能。使用有条件的“颞空间”遗传学方法，该方法将使我们能够选择性地在24小时内提高SHH表达小脑或海马室内的Purkinje细胞，我们将确定小脑SHH表达是必需的和/或足以纠正在海马测试中成年TS65DN小鼠的行为和生理学，还是在大脑的其他部分中进行SHH作用（特定的AIM AIM 2）。