Project 2 - The role of Foxn1 in controlling the transition from thymus expansion to homeostasis
项目 2 - Foxn1 在控制胸腺扩张到稳态转变中的作用
基本信息
- 批准号:10689296
- 负责人:
- 金额:$ 57.98万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AdolescentAdultAffectAge MonthsAllelesBioinformaticsBiometryBordetella pertussisCell CompartmentationCell Differentiation processCell physiologyCellsCharacteristicsCommunicable DiseasesCyclin-Dependent KinasesDataE2F transcription factorsEpithelial Cell ProliferationFamily memberFetal DevelopmentGene ExpressionGenesGenetic TranscriptionGoalsGrowthHomeostasisHumanImmune responseInfluenzaLongevityMapsMemoryMusNeonatalOrganOrgan SizeOrganizational ChangePerinatalPeripheralPertussisPhenotypePopulationProcessProliferatingPublishingRegulationRetinoblastomaRetinoblastoma ProteinRoleStromal CellsStromal ChangeT-LymphocyteTestingThymic epithelial cellThymus GlandTissue imagingTransgenic OrganismsVaccinationcell typecritical periodfetalgain of functionimmune functionloss of functionmouse modelmultiplexed imagingmutantneonatal periodoverexpressionpathogenperinatal periodpostnatalprogenitorprogramsresponseretinoblastoma pathwaysingle-cell RNA sequencingtranscription factor
项目摘要
Abstract
There is growing evidence that thymic epithelial cells (TEC) are the key cell type responsible for orchestrating
the fetal development and postnatal function. A single transcription factor, FOXN1, is known to be a critical
regulator of multiple aspects of TEC proliferation and function throughout the lifespan. The TEC compartment
switches from a fetal/neonatal expansion program to a juvenile homeostasis program, with a key transition point
occurring at about 7 days postnatal in mice (P07), and about 4 months of age in humans. Data in mice show that
this switch is controlled by the retinoblastoma (RB) pathway, acting at least in part by suppression of Foxn1 gene
expression by E2F transcription factors. Mice deficient for multiple RB family members fail to make this switch
and continue to expand. The K5.D1 transgenic line, in which CyclinD1 is specifically overexpressed in TEC,
mimics this RB loss of function phenotype by activating cyclin-dependent kinases that inhibit RB function. In both
RB mutants and K5.D1 transgenics Foxn1 gene expression is elevated, and suppressing Foxn1 expression
using a postnatal-specific hypomorphic allele (Foxn1Z/Z) restores the fetal to juvenile switch, normalizing thymus
size. We have also shown that Foxn1 regulation of TEC proliferation occurs primarily in MHCIIlo TEC, consistent
with preliminary data from the Richie lab that a Sca1-MHCIIlo TEC subset may contain a key proliferating
progenitor population during the switch from fetal expansion to juvenile homeostasis. These data suggest that
during the perinatal to juvenile transition, RB proteins modulate Foxn1 transcription via E2F transcription factors
differentially in specific TEC subsets to ‘put the brakes on’ TEC proliferation, and thus regulate organ size. There
is also growing evidence that the neonatal and adult thymi have stage-specific functions that generate distinct T
cell populations. As FOXN1 is also known to be a key regulator of TEC differentiation, the changes in how Foxn1
expression is regulated to control TEC proliferation should also have significant impacts on TEC function in the
neonatal and adult thymus. We propose three specific aims to test the hypothesis that the RB-dependent
changes in Foxn1 gene expression levels during the neonatal period that are essential for establishing organ
homeostasis are also required to generate specific microenvironments that are necessary for neonatal-specific
organ functions. The goals of this project are to determine: how changes in Foxn1 expression across this
transition impact stromal composition changes in mouse, and compare to stromal changes in human thymus;
how Foxn1 expression is regulated by the RB pathway during this transition; and how these Foxn1-dependent
processes impact immune function.
摘要
越来越多的证据表明,胸腺上皮细胞(TEC)是负责协调
胎儿发育和产后功能。已知一个转录因子FOXN 1是一个关键的转录因子。
TEC增殖的多个方面的调节剂和在整个生命周期中的功能。TEC隔间
从胎儿/新生儿扩张计划切换到青少年体内平衡计划,具有关键的过渡点
小鼠出生后约7天(P0.07),人类出生后约4个月。小鼠实验数据显示,
这种开关由视网膜母细胞瘤(RB)通路控制,至少部分通过抑制Foxn 1基因起作用
通过E2 F转录因子表达。缺乏多个RB家族成员的小鼠不能进行这种转换
并继续扩张。其中CyclinD 1在TEC中特异性过表达的K5.D1转基因系,
通过激活抑制RB功能的细胞周期蛋白依赖性激酶来模拟这种RB功能丧失表型。无论是
RB突变体和K5.D1转基因Foxn 1基因表达升高,抑制Foxn 1表达
使用出生后特异性亚型等位基因(Foxn 1 Z/Z)恢复胎儿到幼年的转换,使胸腺正常化
尺寸我们还表明,Foxn 1对TEC增殖的调节主要发生在MHCIIlo TEC中,这与Foxn 1对TEC增殖的调节一致。
根据Richie实验室的初步数据,Sca 1-MHCIIlo TEC子集可能包含一个关键的增殖因子,
在从胎儿扩张到幼年稳态的转换过程中,这些数据表明
在围产期到幼年期的过渡期,RB蛋白通过E2 F转录因子调节Foxn 1的转录
在特定的TEC亚群中差异化,以“阻止”TEC增殖,从而调节器官大小。那里
越来越多的证据表明,新生儿和成人胸腺具有阶段特异性功能,
细胞群由于FOXN 1也被认为是TEC分化的关键调节因子,因此FOXN 1如何改变TEC的分化,
调控表达以控制TEC增殖也应该对TEC在细胞中的功能有显著影响。
新生儿和成人胸腺。我们提出了三个具体的目标来检验假设,即RB依赖
新生儿时期Foxn 1基因表达水平的变化对建立器官至关重要
体内平衡也是产生特定微环境所必需的,
器官功能。这个项目的目标是确定:如何在Foxn 1表达的变化,
转换影响小鼠中的基质组成变化,并与人胸腺中的基质变化进行比较;
如何Foxn 1的表达是由RB通路在这个过渡过程中调节;以及这些Foxn 1依赖性
过程影响免疫功能。
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)
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Nancy R Manley其他文献
Foxn1 is required for thymic vascularization
Foxn1 是胸腺血管形成所必需的
- DOI:
- 发表时间:
2009 - 期刊:
- 影响因子:0
- 作者:
Takuya Saiki;Kei Mukohara Takashi Otani;Nobutaro Ban.;T.Kaisho;改正恒康;Nancy R Manley - 通讯作者:
Nancy R Manley
CASA: A new method for quantifying organization
CASA:一种量化组织的新方法
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
Kawakami M;Morita S;Sunohara M;Amano Y;Ishikawa R;Watanabe K;Hamano E;Ohishi N;Nakajima J;Yatomi Y;Nagase T;Fukayama M;Takai D.;井手均,岩瀬正典,中村宇大,藤井裕樹,大隈俊明,城臺環,筒信隆,布井清秀,五島大祐,野原栄,篠原規恭,南昌江,和田美也,横溝由史,菊池正統,野見山理久,中村晋,田代憲司,吉成元孝,北園孝成;Nancy R Manley - 通讯作者:
Nancy R Manley
Foxnl is required for thymic vascularization
Foxnl 是胸腺血管化所必需的
- DOI:
- 发表时间:
2009 - 期刊:
- 影响因子:0
- 作者:
Iwasaki;Y.;et al.;高浜洋介;織田順;善本知広;改正恒康;赤松園子・服部淳子・西原みゆき・山口佳子・岡崎章;Nancy R Manley - 通讯作者:
Nancy R Manley
Nancy R Manley的其他文献
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{{ truncateString('Nancy R Manley', 18)}}的其他基金
iTEC as a new experimental system for TEC biology
iTEC 作为 TEC 生物学的新实验系统
- 批准号:
10373479 - 财政年份:2021
- 资助金额:
$ 57.98万 - 项目类别:
iTEC as a new experimental system for TEC biology
iTEC 作为 TEC 生物学的新实验系统
- 批准号:
10493405 - 财政年份:2021
- 资助金额:
$ 57.98万 - 项目类别:
Project 2 - The role of Foxn1 in controlling the transition from thymus expansion to homeostasis
项目 2 - Foxn1 在控制胸腺扩张到稳态转变中的作用
- 批准号:
10022938 - 财政年份:2020
- 资助金额:
$ 57.98万 - 项目类别:
Project 2 - The role of Foxn1 in controlling the transition from thymus expansion to homeostasis
项目 2 - Foxn1 在控制胸腺扩张到稳态转变中的作用
- 批准号:
10251298 - 财政年份:2020
- 资助金额:
$ 57.98万 - 项目类别:
Identifying new genes involved in thymic involution
鉴定参与胸腺退化的新基因
- 批准号:
9909275 - 财政年份:2020
- 资助金额:
$ 57.98万 - 项目类别:
Identifying new genes involved in thymic involution
鉴定参与胸腺退化的新基因
- 批准号:
10092939 - 财政年份:2020
- 资助金额:
$ 57.98万 - 项目类别:
Project 2 - The role of Foxn1 in controlling the transition from thymus expansion to homeostasis
项目 2 - Foxn1 在控制胸腺扩张到稳态转变中的作用
- 批准号:
10470931 - 财政年份:2020
- 资助金额:
$ 57.98万 - 项目类别:
Project 1: Thymic and peripheral Aspects of T cell Aging and Rejuvenation
项目 1:T 细胞衰老和再生的胸腺和外周方面
- 批准号:
10226921 - 财政年份:2017
- 资助金额:
$ 57.98万 - 项目类别:
Mouse models for TB infection across the lifespan
整个生命周期的结核感染小鼠模型
- 批准号:
8772193 - 财政年份:2014
- 资助金额:
$ 57.98万 - 项目类别:
Molecular mechanisms and epigenetic signatures that specify thymus fate
决定胸腺命运的分子机制和表观遗传特征
- 批准号:
9436424 - 财政年份:2014
- 资助金额:
$ 57.98万 - 项目类别:
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