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：
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
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：
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&apos 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

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.

项目概要唾液具有许多极其重要的生物功能，有助于维持口腔功能。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）虽然尚未发现可以解释发病机制的基因突变。干燥综合征 (SS) 的发生，最近的证据表明 T17 细胞浸润并诱导唾液腺腺泡细胞凋亡可能是导致唾液腺损伤的两个主要事件然而，其分子机制涉及T细胞的激活和唾液细胞凋亡。腺泡细胞不对称，与其他自身免疫性疾病相似，女性已被证明是对称的。 SS 患者多于男性，超过 90% 的 SS 病例是在解释这种性别差异的一个假设是 X 染色体随机失活的丧失。可能是这种疾病的原因（因为许多涉及免疫功能的基因在X-上表达）染色体）；然而，X 染色体失活的原因尚不清楚。自身免疫性疾病，包括 SS。我们正在进行的研究获得的结果表明，一系列关键因素在 SS 患者中观察到表观遗传变化，这是一组重要基因转录的结果。此外，XIST1 表达的丧失可能会降低。对于随机 X 染色体失活至关重要）可能会导致 X 染色体上某些基因的激活增加 T 细胞活化并引发细胞凋亡的染色体，此外，大部分丢失。在 CpG 岛中发现 X 染色体上的甲基化，这可能导致染色体不稳定为了进一步了解该机制，我们对RNA进行了全局分析。对照和 SS 样本，并已鉴定出存在于 X 上的主调控基因 ELF4 染色体上调（由于 X 染色体失活的损失）并且可能有助于病理学 SS。这些结果是新颖的，表明 SS 具有很强的表观遗传起源，但还需要进一步研究。因此，在这项拨款提案中，我们打算彻底描述表观遗传学的作用。唾液腺破坏的变化并确定异常甲基化与 X- 之间的关系本研究的假设是表观遗传随着 X- 的丢失而发生变化。染色体失活会改变 ELF4，从而增加对免疫变化的敏感性并促进细胞凋亡腺泡细胞，从而导致唾液腺破坏，从而确定其机制。导致唾液腺破坏的途径可以作为唾液腺中的药物靶标我们将协调我们的努力，以确定抑制的功能意义。我们的研究结果是为了防止唾液腺破坏而发生表观遗传变化。有望为表观遗传变化的作用和涉及的分子机制提供新的见解更好地了解这些事件对于阐明新疗法非常重要。适用于唾液腺功能障碍和 Sjögerns 患者。

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）

Calcium Signaling Regulates Autophagy and Apoptosis.

钙信号调节自噬和细胞凋亡。

DOI：
发表时间：
2021
期刊：
影响因子：
6
作者：
Sukumaran, Pramod;Nascimento Da Conceicao, Viviane;Sun, Yuyang;Ahamad, Naseem;Saraiva, Luis R;Selvaraj, Senthil;Singh, Brij B
通讯作者：
Singh, Brij B

TRPC1 intensifies house dust mite-induced airway remodeling by facilitating epithelial-to-mesenchymal transition and STAT3/NF-κB signaling.

TRPC1 通过促进上皮间质转化和 STAT3/NF-κB 信号传导来强化屋尘螨诱导的气道重塑。

DOI：
发表时间：
2019
期刊：
影响因子：
0
作者：
Pu, Qinqin;Zhao, Yuanyu;Sun, Yuyang;Huang, Ting;Lin, Ping;Zhou, Chuanmin;Qin, Shugang;Singh, Brij B;Wu, Min
通讯作者：
Wu, Min

The TRPC1 Ca2+-permeable channel inhibits exercise-induced protection against high-fat diet-induced obesity and type II diabetes.

TRPC1 Ca2 通透性通道可抑制运动引起的针对高脂肪饮食引起的肥胖和 II 型糖尿病的保护作用。

DOI：
发表时间：
2017
期刊：
影响因子：
0
作者：
Krout, Danielle;Schaar, Anne;Sun, Yuyang;Sukumaran, Pramod;Roemmich, James N;Singh, Brij B;Claycombe
通讯作者：
Claycombe

TRPC1 expression and function inhibit ER stress and cell death in salivary gland cells.

TRPC1 表达和功能抑制唾液腺细胞中的 ER 应激和细胞死亡。

DOI：
发表时间：
2019-01
期刊：
影响因子：
2.7
作者：
Sukumaran, Pramod;Sun, Yuyang;Zangbede, Fredice Quenum;da Conceicao, Viviane Nascimento;Mishra, Bibhuti;Singh, Brij B
通讯作者：
Singh, Brij B

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：
发表时间：
2019
期刊：
影响因子：
4
作者：
Schaar, Anne;Sun, Yuyang;Sukumaran, Pramod;Rosenberger, Thad A;Krout, Danielle;Roemmich, James N;Brinbaumer, Lutz;Claycombe;Singh, Brij B
通讯作者：
Singh, Brij B