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Therapeutic Potential and Mechanisms of Tau Reduction in Autism Models

自闭症模型中 Tau 蛋白减少的治疗潜力和机制

基本信息

批准号：
10394402
负责人：
Lennart Mucke
金额：
$ 71.71万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-03 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394402
关键词：
Ablation Address Adult Adverse effects Affect Age Anatomy Antisense Oligonucleotides Behavior Behavioral Behavioral Symptoms Brain Brain region Cerebrum Child Cognitive deficits Communication Corpus striatum structure Data Development Diagnosis Disease Disease model Electrophysiology (science)Elements Epidemic Epilepsy FRAP1 gene Family Genetic Histologic Human Impairment Injections Intervention Intractable Epilepsy Life Lifestyle-related condition Light Link Longevity MAPT gene Mediating Methods Microtubule-Associated Proteins Modeling Molecular Morphology Mus Mutation Neurodegenerative Disorders Neurons PTEN gene Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Physiological Population Prefrontal Cortex Premature Mortality Prevention Process Property Refractory Role Seizures Signaling Molecule Social Interaction Symptoms Synapses Syndrome Testing Therapeutic Therapeutic Intervention Time United States Viral autism spectrum disorder behavioral impairment behavioral phenotyping clinical development disability disorder subtype dravet syndrome early childhood effective therapy epileptic encephalopathies experimental study individuals with autism spectrum disorder innovation insight knock-down loss of function mutation mouse model network dysfunction neural network novel strategies optogenetics prevent repetitive behavior social social deficits tau Proteins tau expression treatment strategy

项目摘要

PROJECT SUMMARY The autism spectrum disorders (ASDs) affect 1% of the world’s population. The syndromes in this diverse family of disorders share three core features: impaired social interactions, communication deficits, and repetitive behaviors. In the United States, 1 in 68 children are now diagnosed with ASDs, a drastic increase over the last few decades. Despite the perceived “epidemic” of ASDs, there are few effective treatments. In roughly 30% of patients, ASD is associated with epilepsy that is often also refractory to available treatments. Thus, there is an urgent need to develop better treatments for these challenging conditions. The core symptoms of ASDs are common in Dravet syndrome, an intractable epilepsy with onset in early childhood. We recently demonstrated that genetic reduction of tau, a microtubule-associated protein implicated in neurodegenerative disorders, prevents or markedly reduces epileptic seizures, cognitive deficits, and premature mortality in a model of Dravet syndrome (Scn1aRX/+ mice). More surprisingly, we found that tau reduction ameliorated social impairments, communication deficits, and repetitive behaviors in these mice. Genetic reduction of tau also ameliorated similar communication deficits and repetitive behaviors in a separate model of ASD (Cntnap2–/– mice). Encouragingly, genetic tau reduction was well tolerated throughout the lifespan, tau knockdown initiated in adulthood also did not cause obvious adverse effects, and complete ablation was not necessary, as even partial tau reduction provided substantial benefit. These data led to our central hypothesis that tau reduction counteracts ASD pathogenesis and may be developed into an effective treatment for several of these conditions. However, several key issues must be resolved before this strategy is ready for clinical development. To determine whether ASD subtypes that do not include epilepsy may benefit from such a treatment approach, we will examine whether genetic ablation of tau prevents or reduces autism-like behaviors in a third independent mouse model of genetically determined ASD that does not develop epilepsy, Shank3B–/– mice. In addition, an ideal ASD therapy would be effective even if it was administered after symptoms become apparent. To test this possibility, we will knock down cerebral tau expression in Scn1aRX/+ mice with antisense oligonucleotides after autism-like behaviors have become manifest. Finally, we will test hypotheses about the molecular, cellular, and circuit mechanisms by which tau reduction counteracts the core symptoms of ASD. In the long run, our aim is to enable tau reduction to be developed into a treatment for multiple ASDs. By determining the consequences of tau reduction on molecular regulators of development, circuit connectivity, and neuronal properties, we may also identify additional entry points for therapeutic intervention, to the benefit of patients affected by ASDs or other devastating diseases associated with tau-dependent neural network dysfunction.

项目总结：自闭症和自闭症谱系障碍(ASD)将影响世界上约1%的贫困人口。这些症状是多样的。精神障碍的家庭成员有三个共同的核心特征：精神障碍和社交障碍、沟通障碍和精神障碍。重复的行为。在美国北部，现在每68名儿童中就有1人被诊断出患有自闭症，发病率急剧上升。在过去的几十年里，尽管人们认为自闭症是一种流行的疾病，但几乎没有有效的治疗方法。大约30%的患者患有自闭症，这与癫痫有关，而癫痫通常也是难治性疾病，无法找到有效的治疗方法。因此，我们迫切需要为这些具有挑战性的疾病条件开发更好的治疗方法。自闭症的核心症状是Dravet综合征的常见症状，是一种难治性的癫痫样疾病，发病于早期。儿童期。我们最近发现，一种与微管相关的蛋白质Ttau的遗传基因减少与此有关。在神经退行性疾病中，它能显著预防癫痫发作，减少癫痫发作，减少认知功能障碍。在一种新的德拉韦特综合征模型鼠(Scn1aRX/+小鼠)中出现了过早的死亡。更令人惊讶的是，我们发现Ttau的存在。减少和改善了这些小鼠的社会行为障碍、沟通障碍和重复的行为。在另一项单独的研究中，Ttau基因的减少也改善了类似的沟通障碍和重复的行为。 ASD(cntnap2-/-)小鼠的模型。令人鼓舞的是，在整个研究过程中，这种遗传的tau基因减少是很好的，也是很好的耐受。寿命、击倒和在成年后启动的测试也没有造成明显的不良反应，而且完成了。消融手术并不是完全必要的，因为即使是部分消融也能带来实质性的医疗好处。这些数据导致了我们的研究。中央银行假说认为，牛磺酸的减少可以抵消ASD的发病机制，并可能进一步发展为ASD。对于这些疾病中的几种情况，有效的治疗方法是有效的。然而，在这一医疗战略尚未为临床药物开发做好准备之前，必须首先解决几个关键的医疗问题。确定ASD是否有包括癫痫在内的亚型，这样的治疗方法可能不会让他们受益。他们将在三分之一的独立研究中检查基因消融术是否可以预防或减少类似自闭症的行为。用Shank3B/-小鼠建立的遗传决定的ASD小鼠模型表明，他们不会患上癫痫。此外，还有一种新的研究方法。理想的ASD治疗方法即使是在症状变得更加明显后继续使用也不会非常有效。请继续测试这一方法。有可能，我们将不再用反义寡核苷酸修饰的Scn1aRX/+小鼠的大脑中Ttau基因的表达。类似自闭症的行为已经变得越来越明显。最后，我们将测试关于分子、细胞、细胞和基因的假说。电路控制机制是由以下几个方面组成的：它可以减少和抵消ASD的核心症状。从长远来看，我们的目标是。为了更好地使TAU减量能够发展成为治疗多发性ASD的有效治疗方案，我们将通过进一步确定其后果来实现。我们可能会发现，由于分子生物学监管机构对生物发展、电路连接、神经元胞核特性的限制，tau的减少是不可能的。还将确定额外的治疗和干预措施的切入点，以提高受ASDS或其他疾病影响的患者的整体利益。其他毁灭性的疾病与tau依赖的神经营养网络和功能障碍有关。