Delineating contributions of PI3K signaling to neurodevelopmental consequences of Pten haploinsufficiency

描述 PI3K 信号传导对 Pten 单倍体不足的神经发育后果的贡献

• 批准号: 10595844
• 负责人: Damon Theron Page
• 金额: $ 32.66万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10595844
• 关键词: Delineating; contributions; PI3K; signaling; neurodevelopmental

Project Summary/Abstract Autism spectrum disorder (ASD) is a remarkably heterogeneous collection of conditions that converge on the symptoms of social and communication difficulties, together with restricted interests and repetitive behavior. Underlying this heterogeneity is likely a variety of etiologies. Thus, it has become clear in recent years that a “one-size-fits-all” approach to treating ASD is not sufficient. Rather, stratifying individuals based on particular risk factors and symptoms is increasingly being explored as a way to develop targeted personalized treatments for ASD. One risk factor that is receiving significant attention in this context is mutations in the gene PTEN, which encodes a key regulator of growth in the developing body and brain. Germline heterozygous mutations in this gene, which generally reduce levels of PTEN protein, are common in individuals with ASD and macrocephaly (overgrowth of the head and brain). Our laboratory has shown that mice carrying equivalent mutations in Pten display both brain overgrowth and social behavioral deficits, establishing that a reduction in Pten protein level is sufficient to cause ASD-relevant symptoms in an animal model. Pten encodes a phosphatase that acts as a negative regulator of the enzyme phosphoinositide 3-kinase (PI3K), and dysregulation of the PI3K-Akt-mTOR pathway has been linked with neurodevelopmental pathobiology across a variety of preclinical models of ASD. Much attention has been given to inhibition of mTOR, and in particular mTOR complex 1 (mTORC1), as a strategy for treating the neurodevelopmental phenotypes arising from mutations in PTEN and other regulators of the PI3K-Akt-mTOR pathway. In contrast, the therapeutic potential of PI3K inhibition is underexplored, and has not been tested in validated in vivo preclinical models of Pten haploinsufficiency. This project aims to address this problem and to delineate the contributions of PI3K signaling to neurodevelopmental phenotypes resulting from Pten haploinsufficiency. Our overarching hypothesis is that treatment of Pten+/- mice via PI3K inhibition during development will rescue ASD-relevant phenotypes by normalizing downstream signaling. The two aims of this proposal will test this hypothesis through genetic suppression of PI3K in Pik3ca; Pten compound mutant mice (Aim 1) and through treating Pten haploinsufficient mice with a pharmacological PI3K inhibitor at distinct time windows during development to identify a critical period for treatment (Aim 2). For both aims, robust and reproducible ASD-relevant neuroanatomical and behavioral phenotypes in Pten haploinsufficient mice will be used as readouts. Key outcomes of this work will include preclinical testing of PI3K inhibition as a potential therapeutic approach to correct the neurodevelopmental consequences of PTEN mutations and the identification of a critical period when treatment may lead to a suppression of ASD-relevant symptoms.

项目总结/摘要 自闭症谱系障碍（ASD）是一个非常异质性的条件集合，集中在 社交和沟通困难的症状，以及兴趣受限和重复行为。 这种异质性的基础可能是多种病因。因此，近年来已经很清楚， “一刀切”的方法治疗ASD是不够的。相反，根据特定的 风险因素和症状越来越多地被探索作为一种方式来开发有针对性的个性化治疗 自闭症在这种情况下，一个受到极大关注的风险因素是基因PTEN的突变， 它编码了发育中的身体和大脑的关键生长调节因子。生殖系杂合突变 这种基因通常降低PTEN蛋白水平，在ASD患者中很常见， 大头畸形（头部和大脑过度生长）。我们的实验室已经证明，携带相当于 Pten的突变显示大脑过度生长和社会行为缺陷，这表明， Pten蛋白水平足以在动物模型中引起ASD相关症状。Pten编码一个 磷酸酶，其充当磷酸肌醇3-激酶（PI 3 K）的负调节剂，和 PI 3 K-Akt-mTOR通路的失调与神经发育病理学有关， ASD的各种临床前模型。已经对mTOR的抑制给予了很多关注，特别是 mTOR复合物1（mTORC 1），作为治疗由以下引起的神经发育表型的策略： PTEN和PI 3 K-Akt-mTOR通路的其他调节因子中的突变。相反，治疗潜力 PI 3 K抑制的研究不足，并且尚未在Pten的经验证的体内临床前模型中进行测试 单倍不足本项目旨在解决这一问题，并描述PI 3 K的贡献 信号传导至由Pten单倍不足引起的神经发育表型。我们的总体 假设在发育期间通过PI 3 K抑制治疗Pten+/-小鼠将挽救ASD相关 通过使下游信号正常化来进行表型分析。本提案的两个目标将检验这一假设 通过在Pik 3ca; Pten复合突变小鼠（Aim 1）中对PI 3 K的遗传抑制以及通过治疗Pten 在发育过程中的不同时间窗用药理学PI 3 K抑制剂处理单倍型不足小鼠， 确定治疗的关键时期（目标2）。对于这两个目标，稳健和可重复的ASD相关 Pten单倍不足小鼠的神经解剖学和行为表型将用作读数。 这项工作的关键成果将包括PI 3 K抑制作为潜在治疗方法的临床前测试 纠正PTEN突变的神经发育后果，并确定一个关键时期， 治疗可能导致ASD相关症状的抑制。