Epigenetic regulations in Sjogern's syndrome

干燥综合征的表观遗传调控

• 批准号: 10205023
• 负责人: Brij B Singh
• 金额: $ 36.22万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10205023
• 关键词: Acinar Cell; Affect; American; Apoptosis; Applications Grants; Autoantigens; Autoimmune; Autoimmune Diseases; Bacterial Infections; Biological Markers; Biological Process; Biological Response Modifiers; Cell physiology; Cells; Chromosomal Instability; Chromosomal Loss; Collaborations; CpG Islands; Cytotoxic T-Lymphocytes; DNA; Data; Development; Diagnosis; Disease; Drug Targeting; Environmental Risk Factor; Epigenetic Process; Etiology; Event; Female; Functional disorder; Gene Expression; Gene Mutation; Genes; Genetic Predisposition to Disease; Genetic Transcription; Head and Neck Cancer; Head and neck structure; Hypermethylation; Immune; Immune response; Induction of Apoptosis; Infiltration; Inflammation; Lead; Methylation; Molecular; Oral health; Outcome; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Predisposition; Production; Promoter Regions; Radiation therapy; Regulation; Regulator Genes; Research; Role; Saliva; Salivary Glands; Sampling; Series; Sjogren' s Syndrome; Syndrome; T-Cell Activation; T-Lymphocyte; Testing; Virus Diseases; Woman; X Chromosome; X Inactivation; alpha-SNAP; cancer therapy; cytokine; epigenetic regulation; epigenome; gender difference; gene repression; histone modification; immune function; imprint; insight; male; malignant mouth neoplasm; novel; novel therapeutics; perforin; promoter; salivary acinar cell; side effect; therapeutically effective; tool; transcriptome sequencing

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 唾液执行许多非常重要的生物学功能，这些功能有助于维持口服 健康。据估计，美国有超过500万人患有唾液腺功能障碍 （Sjogren综合征）。尽管尚未鉴定出可以解释发病机理的基因突变 在Sjogren综合征（SS）中，最近的证据表明T17细胞浸润和诱导 唾液腺腺泡细胞的凋亡可能是可能导致唾液腺的两个主要事件 破坏。然而，参与T细胞激活的分子机制和唾液的凋亡 腺泡细胞尚不清楚。有趣的是，类似于其他自身免疫性疾病，女性已被证明是 与男性相比，SS的影响更大，其中90％以上的SS病例被诊断出 女性。解释这种性别差异的一种假设是随机X染色体失活的丧失 可能是这种疾病的原因（因为许多参与免疫功能的基因在x-上表达 染色体）;但是，X染色体失活的原因尚不清楚 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一系列关键 SS患者观察到表观遗传变化。结果，一组必不可少的基因的转录 为了控制适当的免疫反应。此外，XIST1表达的丧失（即 对随机X染色体灭活至关重要）可能导致某些基因在X-上的激活 染色体会增加T细胞活化并启动凋亡。此外，大部分损失 在CPG岛上发现了X染色体上的甲基化，这可能导致染色体不稳定性 和失去印迹。为了进一步了解该机制，我们对 控制和SS样品，并确定了X-上存在的主调节基因ELF4 更新了染色体（由于X染色体灭活的丧失），可以帮助病理学 SS。这些结果是新颖的，并暗示了SS的强大表观遗传学起源，但需要进一步 经过验证。因此，在这项赠款提案中，我们打算彻底表征表观遗传的作用 唾液腺破坏的变化，并确定异常甲基化和X-之间的关系 染色体灭活。这项研究的假设是表观遗传的变化以及X-的丧失 染色体灭活会改变ELF4，从而增加了免疫变化的敏感性并促进凋亡 腺泡细胞，从而导致唾液腺破坏。那是机制的识别 导致唾液腺破坏的途径可以代表唾液腺中的药物靶标 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 预计将提供新的见解，以了解表观遗传变化的作用和涉及的分子机制 唾液腺破坏。对这些事件的更多了解对于阐明新疗法很重要 用于唾液腺功能障碍和Sjögerns患者。

项目成果

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: Journal of cell science
• 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: Cells
• 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

R(h)oad to antitumour therapy.

• DOI: 10.1002/ctd2.160
• 发表时间: 2022-12
• 期刊: Clinical and translational discovery
• 作者: Viviane Nascimento Da Conceicao;B. B. Mishra-B.;Brij B. Singh

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: Autoimmunity
• 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

TRPC Channels and Parkinson's Disease.

• DOI: 10.1007/978-94-024-1088-4_8
• 发表时间: 2017
• 期刊: Advances in experimental medicine and biology
• 作者: Sukumaran P;Sun Y;Schaar A;Selvaraj S;Singh BB
• 通讯作者: Singh BB