Microglial plasticity mechanisms in the developing retina
Microglial plasticity mechanisms in the developing retina
批准号:
10716629
负责人:
Melanie A Samuel
金额:
$52.63万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-09-01 至 2027-01-31
关键词:
AdoptedAnusAstrocytesBiological AssayBlindnessCD47 geneCell physiologyCellsCessation of lifeCuesDataDevelopmentDiabetic RetinopathyDiseaseDisease ProgressionEatingEventExcisionEye diseasesGeneticGenetic TranscriptionGlaucomaGoalsHealthHeterogeneityImmuneImmune signalingKnowledgeLigandsLinkMacrophageMediatingMicrogliaMolecularMusNeuronsOutcomePathologyPathway interactionsPhagocytesPhagocytosisPhagocytosis InhibitionPhosphatidylserinesPhysiologicalPlayPopulationPropertyRetinaRetinal DegenerationRetinal DiseasesRoleSHPS-1 proteinSignal TransductionSpecific qualifier valueSynapsesTestingTherapeuticTimeVariantVisionWorkcell motilitycell regenerationcell typeexperimental studyfunctional plasticitygenetic manipulationmolecular imagingnanoscaleneonatal miceneurotransmissionnovelnovel therapeuticsoverexpressionpermissivenesspreventprogramsreceptorretinal regenerationsingle cell sequencing
中文摘要
项目摘要
小胶质细胞是吞噬细胞,在视网膜发育和眼部疾病中发挥多种关键作用。在
与此同时,它们在功能和分子状态上显示出显著的多样性。这表明,
视网膜中需要一系列小胶质细胞亚型,但将小胶质细胞状态与其功能联系起来的分子
仍然未知。这里的目的是确定指定小胶质细胞状态的分子和细胞机制
视网膜的变化。中心假设是,小胶质细胞吞噬状态是由神经元通过一个
特别是神经元衍生的受体-配体对-信号调节蛋白α(SIRPα)和CD 47。这个受体-
配体对构成小胶质细胞中关键的“不要吃我”抗吞噬信号。初步数据令人惊讶地显示,
然而,神经元源性SIRPα对于调节小胶质细胞吞噬功能和吞噬功能也是至关重要的,
状态神经元SIRPα似乎通过作为诱饵受体阻止小胶质细胞CD 47-SIRPα表达来实现这一点。
信号传导,从而允许视网膜发育期间的小胶质细胞吞噬作用。为了理解这些机制
通过其指定小胶质细胞吞噬状态,并测试神经元SIRPα-CD 47信号转导假说,
提出了三个具体目标。首先,我们将确定神经元SIRPα何时以及如何改变小胶质细胞
多样性和可塑性。这些研究将确定神经元SIRPα是否通过以下方式改变小胶质细胞状态:
调节它们的成熟或通过发育后的变化。其次,我们将定义小胶质细胞如何
协调促进不同生理状态的相互冲突的线索。这些实验将因果地
在小胶质细胞状态选择过程中建立“吃我”和“不吃我”线索之间的关系。三是
将确定依赖于SIRPα驱动的小胶质细胞状态变化的发育事件。这一目标将
定义由神经元SIRPα驱动的小胶质细胞状态变化的功能后果。特别是,我们将测试
星形胶质细胞死亡是否依赖于神经元SIRPα信号,这一假设得到了我们初步数据的支持。
这项工作将是有意义的,因为确定一个神经元衍生的机制,决定小胶质细胞的状态
可塑性出乎意料。因此,这项工作的完成将改变我们理解发展的方式。
信号程序小胶质细胞的结果。这项研究还将为新的治疗选择奠定基础,
改变视网膜小胶质细胞的状态和功能。
英文摘要
PROJECT SUMMARY
Microglia are phagocytic cells that play multiple critical roles in retinal development and ocular diseases. In
parallel, they display remarkable diversity in their functional and molecular states. This suggests that a diverse
portfolio of microglial subtypes is needed in the retina, but the molecules that link microglia state to their function
remain unknown. The objective here is to identify molecular and cellular mechanisms that specify microglia state
changes in the retina. The central hypothesis is that microglia phagocytic states are specified by neurons via a
particular neuron-derived receptor-ligand pair – signal regulatory protein alpha (SIRPα) and CD47. This receptor-
ligand pair constitutes a key “don’t eat me” anti-phagocytic signal in microglia. Preliminary data surprisingly show,
however, that neuron-derived SIRPα is also crucial for regulating microglial phagocytic function and phagocytic
state. Neuronal SIRPα appears to achieve this by acting as a decoy receptor to prevent microglial CD47-SIRPα
signaling, thereby permitting microglia phagocytosis during retinal development. To understand the mechanisms
by which microglia phagocytic states are specified, and to test the neuronal SIRPα-CD47 signaling hypothesis,
three Specific Aims are proposed. First, we will determine when and how neuronal SIRPα alters microglia
diversity and plasticity. These studies will establish whether neuronal SIRPα alters microglia state by
regulating their maturation or by post-developmental changes. Second, we will define how microglia
reconcile conflicting cues that promote different physiological states. These experiments will causally
establish the relationship between ‘eat me’ and ‘don’t eat me’ cues during microglia state selection. Third, we
will Identify developmental events that depend on SIRPα-driven microglial state changes. This aim will
define functional consequences of microglial state changes driven by neuronal SIRPα. In particular, we will test
whether astrocyte death depends on neuronal SIRPα signaling, a hypothesis supported by our preliminary data.
This work will be significant because identification of a neuron-derived mechanism that dictates microglia state
plasticity is unexpected. Thus, completion of this work will change the way we understand how developmental
signals program microglia outcomes. This study will also lay the groundwork for new therapeutic options to
modify retina microglia state and function.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Diversity Supplement (Qudrat Abdulwahab) for Role of pericyte nanotubes in age-related neurovascular dysfunction
-
批准号:10702114
-
项目类别:
-
资助金额:$11.96万
-
财政年份:2022
-
负责人:Melanie A Samuel
-
依托单位:
Dopamine Mediated Control of Retinal Vascular Integrity
-
批准号:10705700
-
项目类别:
-
资助金额:$63.79万
-
财政年份:2022
-
负责人:Melanie A Samuel
-
依托单位:
Role of perictyte nanotubes in age-related neurovascular dysfunction
-
批准号:10452103
-
项目类别:
-
资助金额:$45.5万
-
财政年份:2022
-
负责人:Melanie A Samuel
-
依托单位:
Molecular Basis of Outer Retina Development and Repair
-
批准号:10269817
-
项目类别:
-
资助金额:$11.87万
-
财政年份:2020
-
负责人:Melanie A Samuel
-
依托单位:
Molecular Basis of Outer Retina Development and Repair
-
批准号:10652910
-
项目类别:
-
资助金额:$7.22万
-
财政年份:2019
-
负责人:Melanie A Samuel
-
依托单位:
Molecular Basis of Outer Retina Development and Repair
-
批准号:10652031
-
项目类别:
-
资助金额:$11.87万
-
财政年份:2019
-
负责人:Melanie A Samuel
-
依托单位:
Diversity Supplement (Pilar Andrade) for Molecular Basis of Outer Retina Development and Repair
-
批准号:10428900
-
项目类别:
-
资助金额:$7.22万
-
财政年份:2019
-
负责人:Melanie A Samuel
-
依托单位:
Molecular Basis of Outer Retina Development and Repair
-
批准号:10453570
-
项目类别:
-
资助金额:$38.8万
-
财政年份:2019
-
负责人:Melanie A Samuel
-
依托单位:
Molecular Basis of Outer Retina Development and Repair
-
批准号:10653950
-
项目类别:
-
资助金额:$40.0万
-
财政年份:2019
-
负责人:Melanie A Samuel
-
依托单位:
Molecular Basis of Outer Retina Development and Repair
-
批准号:10206150
-
项目类别:
-
资助金额:$40.74万
-
财政年份:2019
-
负责人:Melanie A Samuel
-
依托单位:
Synaptic Reprogramming of Adult Neurons
-
批准号:9165580
-
项目类别:
-
资助金额:$237.75万
-
财政年份:2016
-
负责人:Melanie A Samuel
-
依托单位:
Molecular Mechanisms of Age-related Synaptic Disorganization
-
批准号:9040073
-
项目类别:
-
资助金额:$24.22万
-
财政年份:2015
-
负责人:Melanie A Samuel
-
依托单位:
Molecular Mechanisms of Age-related Synaptic Disorganization
-
批准号:8485265
-
项目类别:
-
资助金额:$9.73万
-
财政年份:2013
-
负责人:Melanie A Samuel
-
依托单位:
Molecular Mechanisms of Age-related Synaptic Disorganization
-
批准号:8726274
-
项目类别:
-
资助金额:$9.73万
-
财政年份:2013
-
负责人:Melanie A Samuel
-
依托单位:
海外基金