Understanding Lrig1+ in vocal fold epithelium and organoid biology
了解声带上皮和类器官生物学中的 Lrig1
基本信息
- 批准号:10732733
- 负责人:
- 金额:$ 55.22万
- 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:2023-07-01 至 2028-06-30
- 项目状态:未结题
- 来源:
- 关键词:AdultAffectBasal CellBasement membraneBenignBiological AssayBiological MarkersBiologyBromodeoxyuridineCell Differentiation processCellsCellular biologyDataDevelopmental BiologyDiseaseDyesEnsureEosinophilic EsophagitisEpithelial CellsEpitheliumEquilibriumExclusionFunctional disorderGenesGeneticGoalsHealthHistologicHomeostasisHumanHyperplasiaImpairmentIn VitroInflammatoryInflammatory InfiltrateInjuryLabelLamina PropriaLarynxLesionLinkMaintenanceMeasuresMediatingMethodsModelingMolecularMorphogenesisMucous MembraneMusNatural regenerationOrganoidsOutcomePatientsPhysiologicalPolymerase Chain ReactionPopulationProliferatingPropertyQuality of lifeRecoveryResearchRoleSignal TransductionStratified EpitheliumStratified Squamous EpitheliumStratum BasaleStressSystemTissuesUp-RegulationVoiceVoice Disorderscapsulecell typecytokinedaughter celleconomic costepithelial injuryepithelial stem cellhuman modelimprovedin vitro Modelin vivoinflammatory milieuinsightkeratinizationmechanical loadmouse modelnext generation sequencingnotch proteinpersonalized medicinepharmacologicpostnatalprogramspsychologicreconstitutionresponseself-renewalsocialstem cell biologystemnesstissue repairtranscriptomic profilingvocal cord
项目摘要
Project Summary/Abstract:
Voice dysfunction impairs the quality of life of affected patients and treating these disorders is associated with
substantial and far-ranging social, psychological, and economic costs. Vocal fold (VF) inflammatory lesions
cause common voice disorders related to disrupted epithelial homeostasis accompanied by inflammatory
infiltrates and changes in the lamina propria. In studies of the epithelium from elsewhere in the body, cell types
that originate hyperplasic changes are epithelial stem cells. These cells have the capability to self-renew and
give rise to the progeny of differentiated daughter cells which is regulated by the local microenvironment and
cell-autonomously via Notch signaling. Inactivation of Notch1 in the presence of inflammatory cytokines can
lead to epithelial hyperplasia, which can be modeled using in vitro organoids. The overall objective of this
proposal is to provide a comprehensive characterization of VF epithelial stem cells, their requirements for self-
renewal and differentiation under physiological conditions and in response to stress factors, namely injury and
mechanical load, while also creating VF organoids to elucidate molecular mechanisms that underline aberrant
epithelial remodeling as seen in benign inflammatory VF lesions. To achieve our goal we will genetically label
epithelial stem cells targeting the Lrig1 gene that has been linked to stemness properties in majority of epithelia
and our preliminary data show that Lrig1 is also expressed in human and murine VF epithelial cells. In Aim 1,
we will perform transcriptome profiling of murine and human VF Lrig1 cells and measure Lrig1 cell responses
to mechanical load during homeostasis. We will delineate the mechanistic role of murine Lrig1 cells in
homeostasis, and genetically inactivate Notch1 in murine Lrig1 cells to determine its effect on proliferation and
differentiation in vivo. In Aim 2, we will induce VF epithelial injury in a murine model, perform transcriptome
profiling of murine Lrig1 cells and measure their responses to mechanical load during epithelial recovery. We
will determine the functional role of murine Lrig1 cells and Notch1 signaling in re-epithelization. In Aim 3, we
will determine differentiation potential of murine and human VF Lrig1 cells using in vivo subrenal graft assay
and in vitro organoids. We will utilize VF organoids to model Notch-mediated epithelial hyperplasia using
genetic, pharmacologic approaches, and inflammatory cytokines. We will create a reliable culture system that
will improve our understanding of VF epithelial cell biology related to VF inflammatory lesions in the context of
personalized medicine.
项目概要/摘要:
声音功能障碍损害受影响患者的生活质量,治疗这些疾病与
社会、心理和经济代价巨大而深远。声带(VF)炎性病变
引起与上皮稳态破坏相关的常见声音障碍,伴有炎症
浸润和固有层的变化。在对身体其他部位上皮细胞的研究中,
是上皮干细胞。这些细胞具有自我更新的能力,
产生受局部微环境调节的分化子细胞的后代,
通过Notch信令进行小区自主。在炎症细胞因子存在下Notch 1的失活可以
导致上皮增生,这可以使用体外类器官来建模。本报告的总体目标
建议是提供VF上皮干细胞的全面表征,它们对自身免疫的要求,
在生理条件下和响应于应激因素,即损伤和
机械负荷,同时也创造VF类器官,以阐明强调异常的分子机制,
良性炎性VF病变中所见的上皮重塑。为了实现我们的目标,我们将在基因上标记
靶向Lrig 1基因的上皮干细胞,该基因与大多数上皮细胞的干性特性有关
我们的初步数据显示Lrig 1也在人和鼠VF上皮细胞中表达。在目标1中,
我们将对鼠和人VF Lrig 1细胞进行转录组分析,并测量Lrig 1细胞反应,
承受机械负荷的能力我们将描述小鼠Lrig 1细胞在
稳态,并在鼠Lrig 1细胞中遗传标记Notch 1,以确定其对增殖和
体内分化。在目标2中,我们将在小鼠模型中诱导VF上皮损伤,进行转录组学研究,
分析鼠Lrig 1细胞并测量它们在上皮恢复期间对机械负荷的响应。我们
将确定鼠Lrig 1细胞和Notch 1信号传导在再上皮化中的功能作用。在目标3中,我们
将使用体内肾下移植物测定法测定鼠和人VF Lrig 1细胞的分化潜能
和体外类器官。我们将利用VF类器官来模拟Notch介导的上皮增生,
遗传学、药理学方法和炎症细胞因子。我们将建立一个可靠的文化体系,
将提高我们对VF上皮细胞生物学的理解,
个性化医疗
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Vlasta Lungova其他文献
Vlasta Lungova的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
相似海外基金
How Does Particle Material Properties Insoluble and Partially Soluble Affect Sensory Perception Of Fat based Products
不溶性和部分可溶的颗粒材料特性如何影响脂肪基产品的感官知觉
- 批准号:
BB/Z514391/1 - 财政年份:2024
- 资助金额:
$ 55.22万 - 项目类别:
Training Grant
BRC-BIO: Establishing Astrangia poculata as a study system to understand how multi-partner symbiotic interactions affect pathogen response in cnidarians
BRC-BIO:建立 Astrangia poculata 作为研究系统,以了解多伙伴共生相互作用如何影响刺胞动物的病原体反应
- 批准号:
2312555 - 财政年份:2024
- 资助金额:
$ 55.22万 - 项目类别:
Standard Grant
RII Track-4:NSF: From the Ground Up to the Air Above Coastal Dunes: How Groundwater and Evaporation Affect the Mechanism of Wind Erosion
RII Track-4:NSF:从地面到沿海沙丘上方的空气:地下水和蒸发如何影响风蚀机制
- 批准号:
2327346 - 财政年份:2024
- 资助金额:
$ 55.22万 - 项目类别:
Standard Grant
Graduating in Austerity: Do Welfare Cuts Affect the Career Path of University Students?
紧缩毕业:福利削减会影响大学生的职业道路吗?
- 批准号:
ES/Z502595/1 - 财政年份:2024
- 资助金额:
$ 55.22万 - 项目类别:
Fellowship
感性個人差指標 Affect-X の構築とビスポークAIサービスの基盤確立
建立个人敏感度指数 Affect-X 并为定制人工智能服务奠定基础
- 批准号:
23K24936 - 财政年份:2024
- 资助金额:
$ 55.22万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Insecure lives and the policy disconnect: How multiple insecurities affect Levelling Up and what joined-up policy can do to help
不安全的生活和政策脱节:多种不安全因素如何影响升级以及联合政策可以提供哪些帮助
- 批准号:
ES/Z000149/1 - 财政年份:2024
- 资助金额:
$ 55.22万 - 项目类别:
Research Grant
How does metal binding affect the function of proteins targeted by a devastating pathogen of cereal crops?
金属结合如何影响谷类作物毁灭性病原体靶向的蛋白质的功能?
- 批准号:
2901648 - 财政年份:2024
- 资助金额:
$ 55.22万 - 项目类别:
Studentship
Investigating how double-negative T cells affect anti-leukemic and GvHD-inducing activities of conventional T cells
研究双阴性 T 细胞如何影响传统 T 细胞的抗白血病和 GvHD 诱导活性
- 批准号:
488039 - 财政年份:2023
- 资助金额:
$ 55.22万 - 项目类别:
Operating Grants
New Tendencies of French Film Theory: Representation, Body, Affect
法国电影理论新动向:再现、身体、情感
- 批准号:
23K00129 - 财政年份:2023
- 资助金额:
$ 55.22万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
The Protruding Void: Mystical Affect in Samuel Beckett's Prose
突出的虚空:塞缪尔·贝克特散文中的神秘影响
- 批准号:
2883985 - 财政年份:2023
- 资助金额:
$ 55.22万 - 项目类别:
Studentship