项目来源
美国卫生和人类服务部基金(HHS)
项目主持人
MING, GUO-LI
项目受资助机构
UNIVERSITY OF PENNSYLVANIA
立项年度
2022
立项时间
未公开
项目编号
5R35NS09737006
项目级别
国家级
研究期限
未知 / 未知
受资助金额
805000.00美元
学科
NEUROSCIENCES
学科代码
未公开
基金类别
Research Projects
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
参与者
未公开
参与机构
未公开
项目标书摘要：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.
项目官员
LAVAUTE,TIMOTHY M
项目持续时间
06 years
项目负责机构类型
SCHOOLS OF MEDICINE
