Signaling pathways that regulate scaling and regeneration of the cerebellum

调节小脑缩放和再生的信号通路

• 批准号: 9217677
• 负责人: ALEXANDRA L. JOYNER
• 金额: $ 45.3万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9217677
• 关键词: Ablation; Acute; Agonist; Alleles; Anterior; Behavior; Birth; Brain; Cell Death; Cell physiology; Cells; Cerebellar cortex structure; Cerebellum; Cerebral Palsy; Cerebral cortex; Cessation of life; Child; Chronic; Clinical; Cognitive; Cognitive deficits; Congenital cerebellar hypoplasia; Cytoplasmic Granules; Dexamethasone; Diphtheria Toxin; Ensure; Environmental Risk Factor; Equilibrium; Evolution; Experimental Models; Financial compensation; GLI gene; GLI2 gene; Gene Targeting; Genetic; Genetic Recombination; Glucocorticoids; Growth; Hemorrhage; Human; Incidence; Infant; Injury; Interneurons; Language; Ligands; Live Birth; Mosaicism; Motor; Mus; Natural regeneration; Neuroglia; Neurologic Dysfunctions; Neurons; Pathway interactions; Performance; Population; Premature Birth; Process; Production; Prosencephalon; Purkinje Cells; RNA Computations; Recovery; Recruitment Activity; Reporter; Rodent; Rodent Model; Role; SHH gene; Signal Pathway; Signal Transduction; Social Functioning; Stem cells; Tamoxifen; Testing; Third Pregnancy Trimester; Time; Transcription Coactivator; Transplantation; base; cell type; cognitive disability; cognitive function; experimental study; genetic approach; granule cell; high risk; imaging study; improved; in vivo; insight; motor deficit; motor impairment; mouse model; mutant; nestin protein; neural circuit; novel; novel strategies; postnatal; precursor cell; public health relevance; receptor; regenerative; response; social; therapy development; tool; transcription factor; transcriptome sequencing; transdifferentiation; white matter

 DESCRIPTION (provided by applicant): The cerebellum (CB), consisting of 80% of the neurons in the human brain, not only has a major role in balance and motor coordination, but also modulates language, reasoning and social processes via neural circuits that connect throughout the forebrain. The ratio of the number of neurons in the CB to the cerebral cortex is remarkably constant across mammalian species, indicating that interconnected circuits have scaled together during evolution. Since much of CB growth occurs in the third trimester and continues for a year after birth, the CB is particularly vulnerable to clinical and environmental factors. Granule cell production, stimulated Sonic Hedgehog (Shh) secreted by Purkinje cells, accounts for a majority of cerebellar growth during this period. Pre-term babies are at a significantly higher risk of developing cerebellar hypoplasia and neurological dysfunction, likely in part because they receive glucocorticoids. In rodent models, glucocorticoids increase death of granule cell precursors (GCPs) in the external granule cell layer (EGL), through a mechanism that involves altered SHH-GLI signaling. However, our preliminary results and other experimental models have demonstrated that the developing rodent CB has a large capacity to regenerate a depleted EGL. In order to enhance recovery from a transient insult to the developing CB, it is critical to identify the signaling pathways that stimulate compensatory expansion of cells, and ensure that all cell types scale together in order to have normally functioning circuits. We will utilize sophisticated mouse genetics approaches to identify such pathways. Our studies are based on the unique discovery we made that when the anterior EGL of the CB is depleted at birth, cells marked with Nestin-FlpoER in the white matter expand and populate the EGL and then differentiate, producing a major recovery. Our preliminary studies and novel genetic approaches provide a powerful approach for studying the cellular behaviors of normal and mutant Nestin-expressing white matter stem cells in response to depletion of the EGL and discovering the signals that stimulate expansion of white matter stem cells and their population of the EGL. Our studies should provide insights that can be used to develop new approaches for augmenting recovery of the infant CB in the face of premature birth, glucocorticoid treatment or other injuries including hemorrhage. Our specific aims are: Aim 1. To determine the regenerative potential of cerebellar white matter Nestin+ stem cells. Aim 2. To identify signaling pathways which are altered in Nestin+ stem cells during regeneration of the EGL. Aim 3. To test whether SHH signaling or some of the identified pathways enhance recruitment of Nestin+ stem cells to a depleted EGL.

 描述（由申请人提供）：小脑（CB）由人脑中80%的神经元组成，不仅在平衡和运动协调方面发挥重要作用，而且还通过连接整个前脑的神经回路调节语言，推理和社会过程。在哺乳动物物种中，CB与大脑皮层中的神经元数量之比是非常恒定的，这表明相互连接的回路在进化过程中已经扩展到一起。由于大部分CB生长发生在妊娠晚期，并在出生后持续一年，CB特别容易受到临床和环境因素的影响。颗粒细胞的产生，刺激浦肯野细胞分泌的Sonic Hedgehog（Shh），占小脑生长的大部分。早产儿患小脑发育不全和神经功能障碍的风险明显更高，部分原因可能是因为他们接受了糖皮质激素。在啮齿动物模型中，糖皮质激素通过涉及改变SHH-GLI信号传导的机制增加外部颗粒细胞层（EGL）中颗粒细胞前体（GCP）的死亡。然而，我们的初步结果和其他实验模型已经证明，发展中的啮齿动物CB有很大的能力，再生耗尽的EGL。为了增强从对发育中的CB的短暂损伤中的恢复，关键是要确定刺激细胞代偿性扩增的信号传导途径，并确保所有细胞类型一起扩展以具有正常功能的电路。我们将利用复杂的小鼠遗传学方法来确定这些途径。我们的研究基于我们的独特发现，即当出生时CB的前EGL耗尽时，白色物质中标记有Nestin-FlpoER的细胞扩增并填充EGL，然后分化，产生主要恢复。我们的初步研究和新的遗传学方法提供了一个强大的方法来研究正常和突变的巢蛋白表达白色物质干细胞的细胞行为响应EGL的耗尽，并发现刺激扩增的白色物质干细胞和他们的人口的EGL的信号。我们的研究应提供见解，可用于开发新的方法，以增强恢复婴儿CB在面对早产，糖皮质激素治疗或其他伤害，包括出血。我们的具体目标是：目标1。确定小脑白色质Nestin+干细胞的再生潜力。目标2.鉴定EGL再生过程中巢蛋白+干细胞中改变的信号通路。目标3。为了测试SHH信号传导或一些鉴定的途径是否增强巢蛋白+干细胞向耗尽的EGL的募集。