Aire-dependent regulation of spontaneous autoimmune-mediated alopecia
自发性自身免疫介导的脱发的空气依赖性调节
基本信息
- 批准号:10464297
- 负责人:
- 金额:$ 2.68万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-04-01 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdultAffectAlopeciaAlopecia AreataAntigensAutoantigensAutoimmuneAutoimmune DiseasesBindingBiopsyC57BL/6 MouseCD8B1 geneCellsChildClinicalCoculture TechniquesComplexCytotoxic T-LymphocytesDataDermatologyDevelopmentDown-RegulationEpidermisEtiologyExhibitsFDA approvedFemaleFoundationsGeneral PopulationGenetic TranscriptionGoalsHairHair follicle structureHarvestHistopathologyHumanImmuneIndividualInterferon Type IIJanus kinaseLeadLesionMajor Histocompatibility ComplexMediatingMentorsMolecularMonitorMusPathogenesisPatientsPhysiciansPlayPrevalenceProcessRecurrenceRegulationResearchResearch TrainingRiskRoleSTAT proteinSTAT1 geneScalp structureScientistSignal PathwaySingle Nucleotide PolymorphismSkinSolidT-LymphocyteTamoxifenTestingThymic epithelial cellThymus GlandTissuesTranscriptional RegulationUp-RegulationWomanautoreactive T cellcareerchemokineclinical efficacycytokinecytotoxicdefined contributionexperimental studyimprovedinflammatory milieuinhibitorinhibitor therapyinnovationinsightkeratinocytekinase inhibitorlifetime riskloss of function mutationmenmonocytemouse modelnoveloff-label useskin disorderskin lesionsubcutaneous
项目摘要
ABSTRACT
This proposal will enable the applicant to acquire mentored research training and develop into a productive,
independent physician-scientist in the field of dermatology.
Alopecia areata (AA) is an autoimmune skin disease, characterized by patchy non-scarring hair loss, with no
cure. AA is caused by inappropriate activation of autoreactive T cells that target and damage keratinocytes of
anagen hair follicles (HFs) due to the collapse of HF immune privilege (IP). Why anagen HFs undergo IP collapse
is not well-understood. Recently, Janus kinase inhibitors (JAKi) have shown clinical efficacy in AA patients by
suppressing immune-cell activity at the HF, however, JAKi do not work for all AA patients. A better mechanistic
understanding of JAK-STAT regulation can lead to more effective AA treatments. Our preliminary data indicates
that we have a novel AA-like mouse model that exhibits spontaneous alopecia in mice genetically null for
autoimmune regulator (Aire-/-). Aire is a transcriptional regulator expressed in medullary thymic epithelial cells
that eliminates autoreactive T cells. We and others have recently shown that Aire is also expressed in epidermal
and follicular keratinocytes. Increasing clinical evidence also supports the importance of Aire in AA, as patients
with loss-of-function mutations in AIRE have an increased risk of developing AA. We observe adult female
C57BL/6 Aire-/- (germline) mice spontaneously develop AA-like lesions (n=35/73). Skin biopsies from alopecic
Aire-/- mice resemble human AA lesions on macroscopic, histopathologic, and molecular levels. Additionally, we
observed upregulation in JAK-STAT signaling in Aire-/- skin lesions and AIRE-deficient cultured keratinocytes
alongside downregulated expression of PIAS1, a STAT1 inhibitor. These findings suggest that 1) Aire is a
critical regulator of HF IP in AA and 2) AIRE is a key suppressor of JAK-STAT signaling in keratinocytes.
This proposal will address current gaps in our understanding of HF IP and JAK-STAT signaling in AA. In Aim 1,
we hypothesize that the loss of either thymic or keratinocyte Aire contribute to HF IP collapse. To test this, we
will harvest CD8+NKG2D+ T cells from alopecic Aire-/- mice, subcutaneously inject them into Aire+/+ mice and
monitor them for AA onset. Cytolytic T cell activity will be assessed via keratinocyte co-culture experiments. The
results of these studies will reveal whether thymic Aire loss is sufficient to trigger HF IP collapse. In parallel, we
will test whether skin-specific deletion of Aire is sufficient to trigger HF IP collapse by utilizing tamoxifen-treated
Airefl/flK5-CreERT2 mice. In Aim 2, we hypothesize that AIRE contributes to the regulation of IFNγ-JAK-STAT
signaling in cultured keratinocytes. To test this, we will determine how AIRE influences the PIAS1, STAT1, and
the PIAS1-STAT1 complex, assess which AIRE domains are required for JAK-STAT signaling, and identify the
AA cytokines and chemokines expressed by AIRE-/- keratinocytes upon IFNγ stimulation. The results of these
studies will uncover novel regulatory mechanisms of JAK-STAT signaling in AA.
摘要
这项建议将使申请人能够获得指导性的研究培训,并发展成为一个富有成效的,
皮肤科领域的独立医生兼科学家。
斑秃(AA)是一种自身免疫性皮肤病,其特征是斑片状非瘢痕性脱发,
疗方AA是由自身反应性T细胞的不适当激活引起的,这些T细胞靶向并损伤角质形成细胞,
生长期毛囊(HF)由于HF免疫豁免(IP)的崩溃。为什么生长期HF经历IP崩溃
并没有被充分理解。最近,Janus激酶抑制剂(JAKi)已经在AA患者中显示出临床疗效,
然而,JAKi抑制HF处的免疫细胞活性并不对所有AA患者起作用。一个更好的机械
对JAK-STAT调节的理解可以导致更有效的AA治疗。我们的初步数据显示
我们有一种新的AA样小鼠模型,在遗传上无效的小鼠中表现出自发性脱发,
自身免疫调节因子(Aire-/-)。Aire是一种在胸腺髓质上皮细胞中表达的转录调节因子
消除自身反应性T细胞我们和其他人最近发现,Aire也在表皮细胞中表达,
和毛囊角质形成细胞。越来越多的临床证据也支持Aire在AA中的重要性,因为患者
AIRE功能缺失突变的患者患AA的风险增加。我们观察成年女性
C57 BL/6 Aire-/-(生殖系)小鼠自发发生AA样病变(n=35/73)。脱发的皮肤活检
Aire-/-小鼠在宏观、组织病理学和分子水平上与人AA病变相似。另外我们
在Aire-/-皮肤损伤和Aire缺陷培养的角质形成细胞中观察到JAK-STAT信号传导的上调
同时下调PIAS 1(一种STAT 1抑制剂)的表达。这些发现表明:1)Aire是一种
2)AIRE是角质形成细胞中JAK-STAT信号传导的关键抑制剂。
该提案将解决我们对AA中HF IP和JAK-STAT信号传导的理解中的当前差距。在目标1中,
我们推测胸腺或角质形成细胞Aire的缺失导致HF IP塌陷。为了验证这个,我们
将从Alopecic Aire-/-小鼠中收获CD 8 + NKG 2D + T细胞,将其皮下注射到Aire+/+小鼠中,
观察他们是否出现AA症状将通过角质形成细胞共培养实验评估细胞溶解性T细胞活性。的
这些研究的结果将揭示胸腺Aire丧失是否足以触发HF IP衰竭。同时,我们
将测试皮肤特异性Aire缺失是否足以通过使用他莫昔芬治疗的HF IP塌陷
Airefl/flK 5-CreERT 2小鼠。在目的2中,我们假设AIRE有助于IFNγ-JAK-STAT的调节
在培养的角质形成细胞中的信号传导。为了验证这一点,我们将确定AIRE如何影响PIAS 1、STAT 1和
PIAS 1-STAT 1复合物,评估JAK-STAT信号传导所需的AIRE结构域,并确定
IFNγ刺激后AIRE-/-角质形成细胞表达的AA细胞因子和趋化因子。的结果予以
研究将揭示AA中JAK-STAT信号传导的新调控机制。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
AIRE Deficiency Leads to the Development of Alopecia Areata‒Like Lesions in Mice.
AIRE 缺乏会导致斑秃的发生,就像小鼠的病变一样。
- DOI:10.1016/j.jid.2022.09.656
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Maglakelidze,Natella;Gao,Ting;Feehan,RobertP;Hobbs,RyanP
- 通讯作者:Hobbs,RyanP
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