权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Deciphering the cellular roles of LIS1 in the mature nervous system

解读 LIS1 在成熟神经系统中的细胞作用

基本信息

批准号：
10586142
负责人：
DEANNA S SMITH
金额：
$ 18.08万
依托单位：
UNIVERSITY OF SOUTH CAROLINA AT COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-03-15 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10586142
关键词：
Actins Adolescent Adult Afferent Neurons Aspiration Pneumonia Astrocytes Autonomic Dysfunction Axon Axonal Transport Brain Brain Diseases Cardiac Myocytes Cell Death Cells Cessation of life Complex Coupled Cytoplasm Defect Dendritic Spines Development Dynein ATPase Epilepsy Exploratory/Developmental Grant Future Genetic Recombination Human Investigation Knockout Mice Kyphosis deformity of spine LIS1 protein Leg Measures Midbrain structure Mitochondria Molecular Molecular Motors Monitor Motor Mus Mutation Myocardium Nerve Degeneration Nervous System Neuroglia Neurologic Neurons Organelles Pathologic Pathology Phenotype Probability Reporting Respiration Risk Rodent Role Seizures Skeletal Muscle Source Spinal Cord Structure Sudden Death Symptoms Synapses Synaptic Transmission Synaptosomes Tail Suspension Tamoxifen Time Work axonal degeneration cell motility cell type dynactin experience experimental study hindbrain insight lissencephaly mouse model predictive modeling promoter response synaptic function

项目摘要

SUMMARY LIS1 mutations can have major pathological effects on human brain development, but we have only a minimal understanding of the postdevelopmental roles of LIS1. LIS1 regulates dynein, a molecular motor that is vitally important for distributing organelles to specific regions in the cell. Neurons in the mature nervous system have extremely long connections called axons that place huge demands on transport motors like dynein. LIS1 depletion in adult mice has severe consequences - mice rapidly develop neurological problems followed by death. We suspect that these severe responses are caused by LIS1 loss in sensorimotor and cardiorespiratory circuits. There was no detectable cell loss or nerve degeneration so we think the problems arise at the level of the synapses, specialized structures that are critical for normal circuits. In Aim 1 we will determine the molecular and cellular changes correlated with the pathological responses, focusing on dynein motors, synapses, and mitochondria, an important dynein cargo. In Aim 2 we propose to deplete LIS1 specifically from neurons (Aim 2A) and a type of glial cell called an astrocyte (Aim 2B). Both cell types express high levels of LIS1, and both contribute to normal synaptic function. We will be able to determine if either are the cellular source of the severe symptoms in the earlier mouse model, or if there are cell type specific symptoms. LIS1 has a known role in axon transport but its function in mature astrocytes has been overlooked in the field. This work will bring new insight into functions of LIS1 in the adult brain.

总结