Epigenetic regulations in Sjogern's syndrome
干燥综合征的表观遗传调控
基本信息
- 批准号:10205023
- 负责人:
- 金额:$ 36.22万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-07-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:Acinar CellAffectAmericanApoptosisApplications GrantsAutoantigensAutoimmuneAutoimmune DiseasesBacterial InfectionsBiological MarkersBiological ProcessBiological Response ModifiersCell physiologyCellsChromosomal InstabilityChromosomal LossCollaborationsCpG IslandsCytotoxic T-LymphocytesDNADataDevelopmentDiagnosisDiseaseDrug TargetingEnvironmental Risk FactorEpigenetic ProcessEtiologyEventFemaleFunctional disorderGene ExpressionGene MutationGenesGenetic Predisposition to DiseaseGenetic TranscriptionHead and Neck CancerHead and neck structureHypermethylationImmuneImmune responseInduction of ApoptosisInfiltrationInflammationLeadMethylationMolecularOral healthOutcomePathogenesisPathologicPathologyPathway interactionsPatientsPharmaceutical PreparationsPhenotypePlayPredispositionProductionPromoter RegionsRadiation therapyRegulationRegulator GenesResearchRoleSalivaSalivary GlandsSamplingSeriesSjogren&aposs SyndromeSyndromeT-Cell ActivationT-LymphocyteTestingVirus DiseasesWomanX ChromosomeX Inactivationalpha-SNAPcancer therapycytokineepigenetic regulationepigenomegender differencegene repressionhistone modificationimmune functionimprintinsightmalemalignant mouth neoplasmnovelnovel therapeuticsperforinpromotersalivary acinar cellside effecttherapeutically effectivetooltranscriptome sequencing
项目摘要
Project Summary
Saliva performs a number of extremely important biological functions that are instrumental in maintaining oral
health. It has been estimated that more than 5 million people in the US suffers from salivary gland dysfunction
(Sjogren's syndrome). Although no genes mutations have been identified that could explain the pathogenesis
of Sjogren's syndrome (SS), recent evidence have suggested that T17-cell infiltration and induction of
apoptosis in salivary gland acinar cells could be the two major events that could lead to salivary gland
destruction. However, the molecular mechanism involved in the activation of T cells and apoptosis of salivary
acinar cells is not known. Interestingly, similar to other autoimmune diseases, females have been shown to be
affected with SS more than their male counterparts, with greater than 90% of SS cases being diagnosed in
women. One hypothesis to explain this gender difference is that loss of random X-chromosome inactivation
could be the cause of this disease (since many genes involved in immune function are expressed on the X-
chromosome); however, the reason for the loss of X-chromosome inactivation is not known in any
autoimmune disease, including SS. Results obtained from our ongoing studies indicate that a series of key
epigenetic changes are observed in SS patients. As a result transcription of a set of genes that are essential
for controlling proper immune response may be decreased. In addition, loss of expression of XIST1 (that is
critical for random X-chromosome inactivation) may lead to the activation of certain genes on the X-
chromosome that increases T cell activation, and initiates apoptosis. Furthermore, most of the loss of
methylation on the X-chromosome was found in the CpG islands, which could lead to chromosomal instability
and loss of imprinting. To further understand the mechanism, we performed a global RNA seq analysis on
control and SS samples and have identified that a master regulator gene ELF4 that is present on the X-
chromosome was upregulated (due to loss of X-chromosome inactivation) and could assist in the pathology of
SS. These results are novel, and suggest a strong epigenetic origin for SS, but they need to be further
validated. Therefore, in this grant proposal we intend to thoroughly characterize the role of epigenetic
changes in salivary gland destruction and to determine the relationship between abnormal methylation and X-
chromosome inactivation. The hypothesis of this study is that epigenetic changes along with the loss of X-
chromosome inactivation alters ELF4 that increases susceptibility to immune changes and promote apoptosis
of acinar cells, thereby leading to salivary gland destruction. Thus, identification of the mechanism as well as
the pathways that lead to salivary gland destruction could represent as drug targets in salivary gland
dysfunction. We will coordinate our efforts in order to determine the functional significance of inhibiting
epigenetic changes in order to protect against salivary gland destruction. The results of our studies are
expected to provide new insights into the role of epigenetic changes and the molecular mechanism involved in
salivary gland destruction. Greater understanding of these events will be important in elucidating new therapy
for salivary gland dysfunctions and Sjögerns patients.
项目摘要
唾液执行许多极其重要的生物功能,这些功能有助于维持口腔健康。
健康据估计,美国有超过500万人患有唾液腺功能障碍
(干燥综合征)。虽然没有发现可以解释发病机制的基因突变
干燥综合征(SS),最近的证据表明,T17细胞浸润和诱导
涎腺腺泡细胞凋亡可能是导致涎腺腺泡细胞凋亡的两个主要事件,
杀伤性然而,涉及T细胞活化和唾液腺细胞凋亡的分子机制尚不清楚。
腺泡细胞未知。有趣的是,与其他自身免疫性疾病相似,女性被证明是
患有SS的女性多于男性,超过90%的SS病例被诊断为
妇女解释这种性别差异的一个假设是,随机X染色体失活的丢失
可能是这种疾病的原因(因为许多参与免疫功能的基因表达在X染色体上,
染色体);然而,X染色体失活丢失的原因在任何研究中都不清楚。
自身免疫性疾病,包括SS。从我们正在进行的研究中获得的结果表明,
在SS患者中观察到表观遗传变化。结果是一组基因的转录,
用于控制适当的免疫反应的能力可能会降低。此外,XIST 1表达的缺失(即,
随机X染色体失活的关键)可能导致X染色体上某些基因的激活,
增加T细胞活化并启动凋亡的染色体。此外,大部分损失
在X染色体上发现CpG岛甲基化,这可能导致染色体不稳定
和印记的丧失。为了进一步了解该机制,我们进行了全球RNA测序分析,
对照和SS样品,并已确定,主调节基因ELF 4,这是目前的X-
染色体被上调(由于X染色体失活的丢失),并可能有助于
SS.这些结果是新的,并提出了一个强大的表观遗传起源的SS,但他们需要进一步
验证.因此,在这项拨款申请中,我们打算彻底描述表观遗传的作用,
唾液腺破坏的变化,并确定异常甲基化与X-
染色体失活这项研究的假设是,表观遗传学的变化沿着X-
染色体失活改变了ELF 4,增加了对免疫变化的易感性并促进了细胞凋亡
腺泡细胞,从而导致唾液腺破坏。因此,该机制的识别以及
导致唾液腺破坏的途径可以作为唾液腺中的药物靶点
功能障碍我们将协调我们的努力,以确定抑制的功能意义,
表观遗传变化,以防止唾液腺破坏。我们的研究结果是
有望为表观遗传变化的作用和参与的分子机制提供新的见解。
唾液腺破坏。更好地理解这些事件将是重要的阐明新的治疗方法
治疗唾液腺功能障碍和舍根氏病
项目成果
期刊论文数量(12)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Ca2+ entry via TRPC1 is essential for cellular differentiation and modulates secretion via the SNARE complex.
Ca2 通过 TRPC1 进入对于细胞分化至关重要,并通过 SNARE 复合体调节分泌。
- DOI:10.1242/jcs.231878
- 发表时间:2019
- 期刊:
- 影响因子:4
- 作者:Schaar,Anne;Sun,Yuyang;Sukumaran,Pramod;Rosenberger,ThadA;Krout,Danielle;Roemmich,JamesN;Brinbaumer,Lutz;Claycombe-Larson,Kate;Singh,BrijB
- 通讯作者:Singh,BrijB
Calcium Signaling Regulates Autophagy and Apoptosis.
- DOI:10.3390/cells10082125
- 发表时间:2021-08-18
- 期刊:
- 影响因子:6
- 作者:Sukumaran P;Nascimento Da Conceicao V;Sun Y;Ahamad N;Saraiva LR;Selvaraj S;Singh BB
- 通讯作者:Singh BB
TRPC Channels and Parkinson's Disease.
- DOI:10.1007/978-94-024-1088-4_8
- 发表时间:2017
- 期刊:
- 影响因子:0
- 作者:Sukumaran P;Sun Y;Schaar A;Selvaraj S;Singh BB
- 通讯作者:Singh BB
Decrease in alpha-1 antiproteinase antitrypsin is observed in primary Sjogren's syndrome condition.
- DOI:10.1080/08916934.2020.1768376
- 发表时间:2020-08
- 期刊:
- 影响因子:3.5
- 作者:Singh BB;Ohm J;Quenum Zanbede FO;Chauhan P;Kroese FGM;Vissink A;Ambrus JL;Mishra BB
- 通讯作者:Mishra BB
R(h)oad to antitumour therapy.
- DOI:10.1002/ctd2.160
- 发表时间:2022-12
- 期刊:
- 影响因子:0
- 作者:Viviane Nascimento Da Conceicao;B. B. Mishra-B.;Brij B. Singh
- 通讯作者:Viviane Nascimento Da Conceicao;B. B. Mishra-B.;Brij B. Singh
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Brij B Singh其他文献
Evidence for the nitrate assimilation-dependent nitrite excretion in cyanobacterium Nostoc MAC
蓝藻发菜 MAC 中硝酸盐同化依赖性亚硝酸盐排泄的证据
- DOI:
- 发表时间:
1996 - 期刊:
- 影响因子:4.1
- 作者:
Brij B Singh;P. K. Pandey;Shailendra P. Singh;P. Bisen - 通讯作者:
P. Bisen
Brij B Singh的其他文献
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{{ truncateString('Brij B Singh', 18)}}的其他基金
Glycolytic metabolites, Calcium entry and Sjogren’s syndrome
糖酵解代谢物、钙进入和干燥综合征
- 批准号:
10583678 - 财政年份:2022
- 资助金额:
$ 36.22万 - 项目类别:
Glycolytic metabolites, Calcium entry and Sjogren’s syndrome
糖酵解代谢物、钙进入和干燥综合征
- 批准号:
10706579 - 财政年份:2022
- 资助金额:
$ 36.22万 - 项目类别:
Ceramide membrane microdomains regulate cytokine secretion
神经酰胺膜微结构域调节细胞因子分泌
- 批准号:
8469388 - 财政年份:2012
- 资助金额:
$ 36.22万 - 项目类别:
Ceramide membrane microdomains regulate cytokine secretion
神经酰胺膜微结构域调节细胞因子分泌
- 批准号:
8374310 - 财政年份:2012
- 资助金额:
$ 36.22万 - 项目类别:
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