Akt-mTOR Pathway Impact on Neural Stem Cell Fates

Akt-mTOR 通路对神经干细胞命运的影响

• 批准号: 9098257
• 负责人: Nathaniel William Hartman
• 金额: $ 38.01万
• 依托单位: RICHARD STOCKTON COLLEGE OF NEW JERSEY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9098257
• 关键词: Address; American; Behavioral; Brain; Cell Cycle; Cell Differentiation process; Cell Proliferation; Cell physiology; Cells; Cognitive deficits; Complex; Data; Development; Disease; Electroporation; FRAP1 gene; Foundations; Functional disorder; Goals; Growth; Intervention; Knowledge; Life; Medical; Molecular; Morphology; Mus; Neonatal; Neurodevelopmental Disorder; Neuroglia; Neurons; Pathology; Pathway interactions; Patients; Pattern; Pharmacologic Substance; Physiological; Plasmids; Production; Proto-Oncogene Proteins c-akt; Regulation; Research; Role; Seizures; Signal Transduction; Social Interaction; Staging; Testing; Transcriptional Regulation; Translating; Tuberous Sclerosis; Tuberous sclerosis protein complex; Vertebral column; Work; autism spectrum disorder; cell behavior; cell motility; density; developmental disease; extracellular; insight; migration; nerve stem cell; neurocognitive disorder; olfactory bulb; postnatal; public health relevance; repaired; repetitive behavior; research study; self-renewal; stem cell differentiation; stem cell fate; subventricular zone; vector

 DESCRIPTION (provided by applicant): Neural stem cells (NSCs) are the building blocks of the brain, lying at the core of brain development, circuit formation and repair. NSCs have the ability to produce more NSCs (self- renew) or give rise to neurons and glial cells (differentiation. Dysfunction in NSC self-renewal and differentiation can result in severe pathologies at various stages of life. The proposed work examines the impact of Akt and mTOR pathway activation on the proliferation and differentiation in postnatal neural stem cells (NSCs). Dysfunction in both Akt and mTOR regulation is known to contribute to the development of Tuberous Sclerosis and Autism Spectrum Disorder in the developing brain. Despite a wealth of studies on brain development, very little is known about the physiological function of Akt-mTOR on NSC fate decisions. Recent studies by the applicant have shown that activation of mTOR Complex 1 (mTORC1) can trigger NSCs to differentiate, increasing neuron production. The objective of the proposed project is to identify the independent physiological functions of Akt and mTOR in NSC proliferation and differentiation. It is hypothesized that Akt activation is necessary to prime NSC for proliferation; while mTOR activation biases NSCs to differentiate into neurons following cell cycle entry. It is also hypothesized that Akt acts through mTOR to increase neuron production, but acts independently to regulate dendritic growth and spine density. To test these hypotheses, a comparison will be made of cell fates, migratory patterns and morphology of the progeny produced by NSCs in three ways: 1) Postnatal electroporation of plasmids that disrupt the Akt and mTOR pathways in the subventricular zone (SVZ) of neonatal mice, 2) ex vivo analysis of transfected cells, and 3) morphological analysis of neurons produced in the olfactory bulb. This project will provide a foundation for further exploration of the downstream targets of Akt signaling as they relate to NSC physiology. The knowledge gained by this project will provide new insight into how Akt-mTOR signaling in NSCs can progress to pathological states observed in diseases like Tuberous Sclerosis and Autism Spectrum Disorder. The long-term goal is to advance understanding of the molecular mechanisms that influence the progression of neurodevelopmental disorders.

 描述（通过应用程序提供）：神经干细胞（NSC）是大脑的基础，位于大脑发育，电路形成和修复的核心。 NSC具有产生更多NSC（自我更新）或引起神经元和神经胶质细胞的能力（分化。NSC自我更新和分化的功能障碍会导致生命的各个阶段的严重病理。拟议的工作研究了Akt和MTOR途径在促进和分化的细胞中的影响（均对后neiriation neyr neyal neronal in neyal neuronal的影响）（ MTOR的调节有助于发展大脑中的结节性硬化和自闭症谱系障碍，但对AKT-MTOR的物理功能很少，而NSC命运的最新研究表明，适用的研究表明，MTOR复杂1（MTORC1）的生产是触发了ness的范围。 Akt和MTOR在NSC增殖和分化中的生理功能。而MTOR激活偏向NSC在细胞周期进入后将NSC分化为神经元。还假设AKT通过MTOR起作用以增加神经元的产生，但独立起作用以调节树突状的生长和脊柱密度。 To test these hypotheses, a comparison will be made of cell fates, migratory patterns and morphology of the progressy produced by NSCs in three ways: 1) Postnatal electroporation of plasmids that disrupt the Akt and mTOR pathways in the subventricular zone (SVZ) of neonatal mice, 2) ex vivo analysis of translated cells, and 3) morphological Analysis of neurons produced in the嗅球。该项目将为与NSC生理学相关的AKT信号的下游目标进一步探索。该项目获得的知识将为NSC中的Akt-MTOR信号传导如何发展为在结节性硬化症和自闭症谱系障碍等疾病中观察到的病理状态的新见解。长期目标是提高对影响神经发育疾病进展的分子机制的理解。