Adherens Junction dysfunction in Hidradenitis Suppurativa
化脓性汗腺炎的粘附连接功能障碍
基本信息
- 批准号:10701323
- 负责人:
- 金额:$ 41万
- 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:2022-09-21 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:AbscessAdherens JunctionAdhesionsAffectArchitectureAxillaBiochemicalBiologicalBloodBullaButtocksCell AdhesionCell-Cell AdhesionChronicCicatrixClinicalComplexCytoplasmDataDevelopmentDiseaseE-CadherinElectron MicroscopyExhibitsFDA approvedFelis catusFunctional disorderFutureGene ExpressionGene Expression ProfileGenetic TranscriptionGoalsHair follicle structureHidradenitis SuppurativaHistologicHomeostasisHumanHyperplasiaImmune responseIn VitroInflammationInflammation MediatorsInflammatoryInguinal regionIntegrinsIntercellular JunctionsKnowledgeLeadLesionLeukocyte ChemotaxisLiquid substanceMapsMechanical StressMechanicsMedicalModelingMolecularMorphologyMusMutationNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNoduleOperative Surgical ProceduresPainPathogenesisPathogenicityPathologyPatientsPopulationProcessProductionProteinsQuality of lifeRecoveryResearchResolutionRoleRuptureSamplingSeverity of illnessSignal PathwaySignal TransductionSkinStructureSuctionSumSymptomsTherapeuticTissuesTranslationsadalimumabappendagechemokinecytokinedemographicsdesmogleineffective therapyexperienceexpression vectorgamma secretasehuman subjectimprovedinsightkeratinocytemouse modelmutantnew therapeutic targetprotein degradationrhoskin disordertargeted treatmenttranscriptomics
项目摘要
Project Summary
Hidradenitis Suppurativa (HS) is a chronic, debilitating inflammatory skin disease that affects the
pilosebaceous units in skin folds in 1-4% of the population. It often leads to disfiguring and permanent scarring.
Histologically, lesions exhibit epidermal hyperplasia, hair follicle abnormalities, and inflammation. HS is
aggravated by mechanical stress1-3. Treatment often involves a combination of surgical and medical
management. Adalimumab, the only FDA-approved therapy, is effective in 20-30% of patients. Gaps in our
understanding of the mechanisms involved in HS preclude the development of more effective and
targeted therapies for this debilitating, under-recognized and often misdiagnosed disease.
We discovered that the expression of E-cadherin (E-cad) and p120 catenin (p120), two critical proteins for
keratinocyte adherens junction (AJ) structure and function, is lost in 19 of 23 samples from severe HS lesions.
Even in non-lesional skin from HS patients, we observe a complete loss or translocation of E-cad or p120 to
the cytoplasm. Moreover, the degree of E-cad or p120 protein loss correlates positively with disease severity.
A role for AJ protein loss in HS is further substantiated by the observation that mice lacking E-cad or p120 in
their skin exhibit HS-like histological features. A key question is whether E-cad and p120 loss contributes to the
disease process through destabilizing keratinocyte cell junctions or whether it results from the inflammatory
process: we posit that it is both.
Here, we will rigorously investigate keratinocytes, not just as innocent bystanders, but as active
contributors to HS pathogenesis. Our data suggest that HS keratinocyte adhesion is at the center of a
pathomechanism characterized by a feed forward cycle in which loss of adhesion drives inflammatory cytokine
expression. Expression of these cytokines further weaken adhesion, which, in turn, drives further expression of
cytokines, leading to loss of homeostasis and more inflammation. Therefore, we propose to delve into this
pathogenic cycle with two synergistic aims using in vitro culture models, murine models, and samples from
human subjects, including keratinocytes, blood, and suction blister fluid from both normal subjects and HS
patients. In Aim 1, we will determine how the loss of E-cad and p120 in HS keratinocytes contributes to HS
pathophysiology. In Aim 2, we will determine how inflammatory mediators of HS induce loss of E-cad, p120
and adhesion in keratinocytes. We will correlate our results with subject demographics and clinical information
to determine any associations with biological variables.
Successful completion of this project will elucidate the mechanism by which keratinocytes contribute to the
pathogenic cycle of inflammation and tissue disruption in HS. This new knowledge is critical to our overall
understanding of HS pathophysiology. Future therapeutic approaches will result from our efforts to discover
new HS pathomechanisms in support of NIAMS goals to improve the treatment for this debilitating disease.
项目摘要
化脓性汗腺炎(HS)是一种慢性、使人衰弱的炎症性皮肤病,
1-4%的人群皮肤褶皱中存在毛囊皮脂腺单位。它往往会导致毁容和永久疤痕。
组织学上,病变表现为表皮增生、毛囊异常和炎症。HS是
机械应力加剧1 -3。治疗通常包括手术和药物的结合
管理阿达木单抗是FDA唯一批准的治疗方法,对20-30%的患者有效。差距在我们
对HS所涉及的机制的理解排除了开发更有效和
针对这种使人衰弱、认识不足和经常误诊的疾病的靶向治疗。
我们发现,E-cad和p120连环蛋白(p120)的表达,这两个关键蛋白,
角质形成细胞粘附连接(AJ)的结构和功能,在23例严重HS病变的样本中有19例丢失。
即使在HS患者的非病变皮肤中,我们也观察到E-cad或p120完全丢失或易位,
细胞质此外,E-cad或p120蛋白丢失的程度与疾病的严重程度呈正相关。
AJ蛋白丢失在HS中的作用进一步被以下观察所证实:
它们的皮肤表现出HS样组织学特征。一个关键的问题是E-cad和p120的缺失是否有助于
疾病的过程是通过破坏角质形成细胞连接的稳定,
过程:我们认为这两者都是。
在这里,我们将严格调查角质细胞,不只是作为无辜的旁观者,但作为积极的
HS发病机制的贡献者。我们的数据表明,HS角质形成细胞粘附是在一个中心,
病理机制特征为前馈循环,其中粘附丧失驱动炎性细胞因子
表情这些细胞因子的表达进一步减弱粘附,这反过来又驱动细胞因子的进一步表达。
细胞因子,导致体内平衡的丧失和更多的炎症。因此,我们建议就此进行深入研究
致病循环,具有两个协同作用的目的,使用体外培养模型、鼠模型和来自
人类受试者,包括来自正常受试者和HS的角质形成细胞、血液和抽吸水疱液
患者在目标1中,我们将确定HS角质形成细胞中E-cad和p120的缺失如何促成HS
病理生理学在目标2中,我们将确定HS的炎症介质如何诱导E-cad,p120的丢失
和角质形成细胞中的粘附。我们将把我们的结果与受试者人口统计学和临床信息相关联
以确定与生物变量的任何关联。
本项目的成功完成将阐明角质形成细胞促进细胞增殖的机制。
HS中的炎症和组织破坏的致病循环。这些新知识对我们的整体
了解HS病理生理学。未来的治疗方法将来自于我们的努力,
新的HS病理机制,以支持NIAMS的目标,以改善这种衰弱性疾病的治疗。
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 }}
Amanda Marie Nelson其他文献
Amanda Marie Nelson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 }}
{{ truncateString('Amanda Marie Nelson', 18)}}的其他基金
Defining the role of Toll-like receptor 3 in skin homeostasis, injury and neoplasia
定义 Toll 样受体 3 在皮肤稳态、损伤和肿瘤中的作用
- 批准号:
9249493 - 财政年份:2016
- 资助金额:
$ 41万 - 项目类别:
Defining the role of Toll-like receptor 3 in skin homeostasis, injury and neoplasia
定义 Toll 样受体 3 在皮肤稳态、损伤和肿瘤中的作用
- 批准号:
9899201 - 财政年份:2016
- 资助金额:
$ 41万 - 项目类别:
Defining the role of Toll-like receptor 3 in skin homeostasis, injury and neoplasia
定义 Toll 样受体 3 在皮肤稳态、损伤和肿瘤中的作用
- 批准号:
9087888 - 财政年份:2016
- 资助金额:
$ 41万 - 项目类别:
Cytokine Regulation of Wound Induced Skin Regeneration
伤口诱导皮肤再生的细胞因子调节
- 批准号:
8457180 - 财政年份:2012
- 资助金额:
$ 41万 - 项目类别:
相似海外基金
Oral pathogen - mediated pro-tumorigenic transformation through disruption of an Adherens Junction - associated RNAi machinery
通过破坏粘附连接相关的 RNAi 机制,口腔病原体介导促肿瘤转化
- 批准号:
10752248 - 财政年份:2024
- 资助金额:
$ 41万 - 项目类别:
Adherens junction dynamics and function in epithelial tissue morphogenesis
粘附连接动力学和上皮组织形态发生中的功能
- 批准号:
469118 - 财政年份:2022
- 资助金额:
$ 41万 - 项目类别:
Operating Grants
Adherens junction proteins in neuron-glia interactions
神经元-胶质细胞相互作用中的粘附连接蛋白
- 批准号:
9978138 - 财政年份:2019
- 资助金额:
$ 41万 - 项目类别:
Elucidation of the function of Focal adherens junction in morphogenesis
阐明焦点粘附连接在形态发生中的功能
- 批准号:
19K16145 - 财政年份:2019
- 资助金额:
$ 41万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Identifying and characterizing the effect of Aip1 on adherens junction remodeling in Drosophila follicular epithelium
鉴定和表征 Aip1 对果蝇滤泡上皮粘附连接重塑的影响
- 批准号:
528450-2018 - 财政年份:2018
- 资助金额:
$ 41万 - 项目类别:
Alexander Graham Bell Canada Graduate Scholarships - Master's
Src-mediated pathways regulating adherens junction assembly.
Src 介导的途径调节粘附连接组装。
- 批准号:
10166863 - 财政年份:2017
- 资助金额:
$ 41万 - 项目类别:
Src-mediated pathways regulating adherens junction assembly.
Src 介导的途径调节粘附连接组装。
- 批准号:
9310733 - 财政年份:2017
- 资助金额:
$ 41万 - 项目类别:
The function and interaction of focal adhesion and adherens junction in bone mechanosensing and mechanotransduction.
粘着斑和粘附连接在骨力传感和力转导中的功能和相互作用。
- 批准号:
17K17307 - 财政年份:2017
- 资助金额:
$ 41万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
a-catenin and its binding partners in adherens junction assembly and function
α-连环蛋白及其在粘附连接组装和功能中的结合伙伴
- 批准号:
357714 - 财政年份:2016
- 资助金额:
$ 41万 - 项目类别:
Operating Grants
Role of adherens junction on cell mechanosensing system in bone
粘附连接对骨细胞机械传感系统的作用
- 批准号:
15K20578 - 财政年份:2015
- 资助金额:
$ 41万 - 项目类别:
Grant-in-Aid for Young Scientists (B)