Non-apoptotic functions of caspase-3 in neural development
Caspase-3在神经发育中的非凋亡功能
基本信息
- 批准号:10862033
- 负责人:
- 金额:$ 47.33万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAcoustic NerveApoptosisApoptoticAppearanceAuditoryAuditory PerceptionAuditory systemAxonBrainBrain StemCASP3 geneCASP6 geneCASP8 geneCASP9 geneCaspaseCategoriesCell DeathCell Death Signaling ProcessCell Membrane PermeabilityCell NucleusCellsCessation of lifeChick EmbryoCochleaCommunicationCytoprotectionDataDefectDendritesDevelopmentDevelopmental ProcessElectroporationEmbryoEmbryonic DevelopmentGangliaGenesGoalsGrowth Associated Protein 43Hearing TestsLanguageMediatingMitochondriaModelingMolecularNCAM1 geneNerveNeuron-Glia Cell Adhesion MoleculesNeuronsNeurosciencesOntologyOuter Mitochondrial MembranePathway interactionsPeptide HydrolasesPermeabilityPlasmidsProcessProteinsProteolysisProteomeProteomicsRegulationResearchRoleSamplingSiteSourceStructural defectSynapsesSystems DevelopmentTestingTimeTransfectionTransplantationWorkauditory pathwayaxon growthaxon guidancecytotoxicexosomeextracellular vesiclesneural circuitneurodevelopmentreceptorsoundtandem mass spectrometryvesicular releasex-linked inhibitor of apoptosis protein
项目摘要
PROJECT SUMMARY
Auditory function relies on highly specialized and precise neuronal connectivity. A significant
challenge for the field of auditory neuroscience is to understand how these neural circuits form during
development. Our previous work suggests an important function for caspase-3, a protease best
known for its role in apoptosis. Cleaved (active) caspase-3 is present in the developing auditory
brainstem prior to the period of programmed cell death. During embryonic development, it is first
seen in auditory nerve axons, then in the synaptic target of these axons in nucleus magnocellularis
(NM), then in the synaptic target of NM, in nucleus laminaris (NL) dendrites. Caspase-3 inhibition
during development results in substantial errors in NM axon targeting and in structural abnormalities
in NL. We propose to investigate the regulation of caspase-3 activation during development. We will
examine the basis for the progression of caspase-3 activation through the auditory pathway and test
the hypothesis that cleaved caspase-3 is necessary in auditory axons for activation of caspase-3 in
their synaptic targets. Caspase-3 activation during apoptosis is activated by cell death signals and
mitochondrial permeabilization. We hypothesize that during auditory development, caspase-3 is
activated through a non-canonical pathway that is protective for cells with cleaved caspase-3 in their
axons. We will test the function of upstream molecules and determine whether they influence
development of the NM-NL pathway. We have begun to investigate the molecules through which
caspase-3 influences auditory development. Our proteomics study revealed hundreds of proteins that
are cleaved by caspase-3 in the developing auditory brainstem. We have identified several substrates
that mediate axon growth. We will use caspase-uncleavable forms of these proteins to test their
caspase-dependent functions in development. Gene ontology analysis revealed that the most
abundant cellular localization category for caspase-3 substrates was exosomes/extracellular vesicles
(EVs). This finding suggests an overarching model in which caspase-3 influences the composition of
EVs, which in turn provide an effective means of local communication between cells during
development. We will examine enriched EV samples using tandem mass spectrometry to determine
which caspase-3 substrates are present in EVs. We will use an EV grafting strategy to investigate
whether EVs can rescue developmental deficits in caspase-3 inhibited host embryos. Together, these
studies will advance our understanding of neural circuit assembly in the developing auditory
brainstem.
项目摘要
听觉功能依赖于高度专业化和精确的神经元连接。显著
听觉神经科学领域面临的挑战是了解这些神经回路是如何形成的,
发展我们以前的工作表明caspase-3的一个重要功能,一种蛋白酶,
以其在细胞凋亡中的作用而闻名。切割(活性)caspase-3存在于发育中的听觉
在程序性细胞死亡之前的脑干。在胚胎发育过程中,它首先
在听神经轴突中可见,然后在这些轴突的大细胞核中的突触靶中可见
(NM)其次是NM的突触靶区、板层核(NL)树突。Caspase-3抑制
导致NM轴突靶向和结构异常的实质性错误
在NL。我们建议研究发育过程中caspase-3激活的调节。我们将
检查通过听觉通路的caspase-3激活进展的基础,
假设切割的caspase-3在听觉轴突中是激活caspase-3所必需的,
它们的突触靶点细胞凋亡过程中的半胱天冬酶-3激活由细胞死亡信号激活,
线粒体透化我们假设在听觉发育过程中,caspase-3是
通过非经典途径激活,该途径对具有切割的caspase-3的细胞具有保护作用,
轴突我们将测试上游分子的功能,并确定它们是否影响
NM-NL途径的发展。我们已经开始研究分子,
caspase-3影响听觉发育。我们的蛋白质组学研究揭示了数百种蛋白质,
在发育中的听觉脑干中被半胱天冬酶-3切割。我们已经确定了几种底物
介导轴突生长。我们将使用这些蛋白质的半胱天冬酶不可切割形式来测试它们的
半胱天冬酶依赖的功能。基因本体分析显示,
caspase-3底物的丰富细胞定位类别是外泌体/细胞外囊泡
(电动汽车)。这一发现表明了一个总体模型,其中caspase-3影响了细胞的组成。
电动汽车,反过来又提供了电池之间本地通信的有效手段
发展我们将使用串联质谱法检查富集的EV样品,
其半胱天冬酶-3底物存在于EV中。我们将使用EV移植策略来研究
EV是否可以挽救caspase-3抑制宿主胚胎的发育缺陷。所有这些
这些研究将促进我们对发育中的听觉神经回路组装的理解。
脑干
项目成果
期刊论文数量(0)
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Karina S Cramer其他文献
Karina S Cramer的其他文献
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{{ truncateString('Karina S Cramer', 18)}}的其他基金
Glial Influences on Auditory Brainstem Development
神经胶质对听觉脑干发育的影响
- 批准号:
8402096 - 财政年份:2011
- 资助金额:
$ 47.33万 - 项目类别:
Glial Influences on Auditory Brainstem Development
神经胶质对听觉脑干发育的影响
- 批准号:
9282739 - 财政年份:2011
- 资助金额:
$ 47.33万 - 项目类别:
Glial Influences on Auditory Brainstem Development
神经胶质对听觉脑干发育的影响
- 批准号:
8210807 - 财政年份:2011
- 资助金额:
$ 47.33万 - 项目类别:
Glial Influences on Auditory Brainstem Development
神经胶质对听觉脑干发育的影响
- 批准号:
9918157 - 财政年份:2011
- 资助金额:
$ 47.33万 - 项目类别:
Glial Influences on Auditory Brainstem Development
神经胶质对听觉脑干发育的影响
- 批准号:
8598827 - 财政年份:2011
- 资助金额:
$ 47.33万 - 项目类别:
Glial Influences on Auditory Brainstem Development
神经胶质对听觉脑干发育的影响
- 批准号:
8039811 - 财政年份:2011
- 资助金额:
$ 47.33万 - 项目类别: