Functional roles of genetic risk factors for brain disorders in neurogenesis and neurodevelopment

脑部疾病遗传危险因素在神经发生和神经发育中的功能作用

• 批准号: 10065021
• 负责人: Guo-li Ming
• 金额: $ 80.5万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065021
• 关键词: Adult; Affect; Animal Model; Behavior; Biological; Biology; Brain; Brain Diseases; Cell Culture System; Cell physiology; Cells; Copy Number Polymorphism; DNA Sequence Alteration; Development; Diagnosis; Disease; Environmental Risk Factor; Event; Generations; Genetic; Genetic Risk; Genetic Variation; Goals; Human; Human Development; Induced pluripotent stem cell derived neurons; Intervention; Knowledge; Measures; Molecular; Mus; Neurodevelopmental Disorder; Neurons; Neurophysiology - biologic function; Patients; Process; Research; Resolution; Resources; Risk; Risk Factors; Role; Technology; Testing; Therapeutic Intervention; Tissues; Transgenic Mice; adult neurogenesis; base; cell behavior; design; differentiation protocol; genetic risk factor; human stem cells; induced pluripotent stem cell; mouse model; nerve stem cell; nervous system disorder; neural model; neurodevelopment; neurogenesis; neuromechanism; neuron development; novel; prevent; programs; relating to nervous system; risk variant; stem cell biology; synaptogenesis; targeted treatment; technological innovation; three dimensional cell culture; tool; transcriptome

The overarching goal of this program is to define cellular and molecular events during neural development vulnerable to genetic perturbations that increase risk for neurodevelopmental and neurological disorders. Currently, our knowledge of human brain development is largely inferred from animal models, indirect measures of human development, and limited access to human neural tissue. All of these are valid tools to piece together the sequential processes of human neural development but are not sufficient to describe the dynamics with enough temporal or molecular resolution to understand mechanistically how genetic risk factors can affect brain formation and function. Technological advances in cellular reprogramming have now made it possible to derive induced pluripotent stem cells (iPSCs) from adult patients, which are a renewable resource for the generation of human neurons with disease-relevant genetic features. This long-term research program is designed to incorporate human iPSC-based studies with animal models to provide a comprehensive and longitudinal understanding of neural development, from neural stem cell behavior to neuronal development, synapse formation and circuit integration. As a proof-of-principle, these studies will use a prominent copy number variation (CNV) risk factor for multiple neurological disorders, 15q11.2CNVs, to illustrate how multifaceted interrogations of the basic biology of neural development in the context of genetic variation can reveal new targets for testing mechanism-based intervention in relevant subtypes of human neurons, as well as animal models of neural function and behavior. Building on significant scientific discoveries we have made in the fields of stem cell biology, adult neurogenesis, and patient-specific iPSCs, and technological innovations we have developed to meet critical challenges in each of these fields, our primary research focus is to integrate multiple levels of analysis to provide a high-resolution description of the cellular processes and molecular mechanisms of neural development that can be used to probe genetic or environmental risk for neurological disorders. Three interlinked projects will be pursued. Project 1 will focus on adult mouse neurogenesis as a model for neural development and use clonal analysis of neural stem cells and their development, single-cell transcriptome analysis, and transgenic mouse models to dissect molecular, cellular, and circuit level effects of genetic mutations on neural development; Project 2 will use human iPSCs with known genetic risk factors, and targeted differentiation protocols, to interrogate human neural development in 2D and 3D cultures; and Project 3 will focus on identifying the molecular mechanisms and targets of risk genes in both animal models and human iPSC-derived neurons and the rescue of observed deficits through rational therapeutic intervention. This is an opportune moment to synthesize recently developed technologies and build a novel translational platform to study underlying mechanisms of neurological disorders, and facilitate the identification of strategies to diagnose, treat, and prevent the often debilitating consequences of dysregulated neural development.

该程序的总体目标是在神经发育过程中定义细胞和分子事件，这些神经发育容易受到遗传扰动的影响，从而增加神经发育和神经系统疾病的风险。当前，我们对人脑发育的了解主要是从动物模型，人类发育的间接度量以及对人类神经组织的获取有限的范围中推断出来的。所有这些都是将人类神经发育的顺序过程拼凑在一起的有效工具，但不足以用足够的时间或分子分辨率来描述动力学，以便从机械上理解遗传危险因素如何影响脑的形成和功能。现在，细胞重编程的技术进步使得从成年患者中得出引起多能干细胞（IPSC）成为可能，这是具有疾病伴有疾病遗传特征的人类神经元的可再生资源。该长期研究计划旨在将基于人类IPSC的研究与动物模型结合在一起，以提供对神经发育的全面和纵向理解，从神经干细胞行为到神经元发展，突触形成和电路整合。 As a proof-of-principle, these studies will use a prominent copy number variation (CNV) risk factor for multiple neurological disorders, 15q11.2CNVs, to illustrate how multifaceted interrogations of the basic biology of neural development in the context of genetic variation can reveal new targets for testing mechanism-based intervention in relevant subtypes of human neurons, as well as animal models of neural function and behavior.基于我们在干细胞生物学，成人神经发生和患者特异性IPSC领域的重要科学发现的基础上，我们已经开发了我们为应对这些领域的关键挑战而开发的技术创新，我们的主要研究重点是整合多个分析以提供对细胞过程的高分辨率和分子机制的高分辨率分析，从而可以使用神经机制来实现NEURENIS型群体的范围，以实现NEUR的依赖性或分子的范围。将追求三个相互联系的项目。项目1将集中于成年小鼠神经发生，作为神经发育的模型，并使用神经干细胞的克隆分析及其发育，单细胞转录组分析以及转基因小鼠模型，以剖析遗传突变对神经发育的分子，细胞和电路水平的影响；项目2将使用具有已知遗传危险因素的人类IPSC，并针对靶向分化方案来询问2D和3D培养物中的人类神经发育；项目3将集中于在动物模型和人IPSC衍生的神经元中识别风险基因的分子机制和靶标，并通过合理的治疗干预措施营救观察到的缺陷。这是综合最近开发的技术并建立一个新型的转化平台来研究神经系统疾病的基本机制，并促进鉴定诊断，治疗和防止神经发育失调常常令人衰弱的后果。