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（由申请人提供）：唐氏综合症 (DS) 由人类 21 号染色体 (Hsa21) 三体性引起，是导致智力障碍的最常见的遗传原因，被认为会导致小脑中的学习问题。对患有 DS 的人的大脑和海马体进行纠正的治疗将明显改善患有 DS 的儿童和年轻人的生活，并使他们能够更好地融入社会。我们最近表明，在出生当天注射 Sonic Hedgehog (Shh) 激动剂 SAG 1.1，可以使小脑的大小和总体解剖结构永久正常化，从而更好地解决成人空间问题，并恢复儿童学习的电生理相关性。 DS 的 Ts65Dn 小鼠模型的 CA1-海马亚区在将这一发现转化为对人类海马行为的治疗之前仍存在许多问题。通过Shh诱导的小脑结构正常化或通过Shh的直接刺激发生的生理学尚不清楚，将Shh治疗推进到临床的另一个限制是这种强效生长因子的广泛影响，这使得在人体中的全身应用存在问题。更有限的药物输送方法可能会限制副作用，另一种方法是了解哪些 Hsa21 基因可以下调小脑中的 Shh 通路反应，这可能会提出更多“可用药”的靶标。使用包含 169 个 cDNA 的 Hsa21 基因表达克隆集筛选 Shh 反应，其中 149 个在人类和小鼠之间高度保守，其中 20 个是人类特有的基因，可在 LIGHT2 测定中显着降低 Shh 通路激活，并将在额外的 Shh- 中进行评估。敏感的检测，以确保它们能够在不同的生物系统中推广（具体目标 1），接下来，我们将确定 Ts65Dn 大脑中 Shh 的区域特异性表达如何影响海马。使用条件“时空”遗传学方法，我们可以在出生时选择性地在 24 小时内增加 Shh 表达。小脑或海马内的浦肯野细胞，我们将确定小脑 Shh 表达是否必要和/或足以纠正海马测试中成年 Ts65Dn 小鼠的行为和生理学，或者是否需要大脑其他部分的 Shh 动作（具体目标 2）。