NIDCR Individual Predoctoral Scientist Fellowship

NIDCR 个人博士前科学家奖学金

• 批准号: 8717277
• 负责人: Marybeth Francis
• 金额: $ 4.85万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-16 至 2019-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8717277
• 关键词: Acceleration; Acetylation; Affect; Animal Model; Animals; Bone Tissue; CCL2 gene; CXCL1 gene; Candidate Disease Gene; Cell Culture System; Cell Nucleus; Cells; Chromatin; Chromatin Structure; Chromosome Mapping; Chronic; Clinical; Collagen; Connective Tissue; Data; Defense Mechanisms; Defensins; Dental Plaque; Diabetes Mellitus; Disease; Disease Pathway; Disease model; ERG gene; Endemic Diseases; Environment; Enzymes; Epigenetic Process; Exposure to; Fellowship; Gene Expression; Gene Expression Microarray Analysis; Gene Expression Profiling; Gene Targeting; Genes; Genetic Transcription; Glucose; Healed; Health; Histones; Human; Hyperglycemia; Immune response; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Interleukins; Lead; Link; Lipopolysaccharides; Lysine; MMP2 gene; Maps; Methylation; Methyltransferase; Microbial Biofilms; Modeling; Modification; Molecular; NF-kappa B; National Institute of Dental and Craniofacial Research; Natural regeneration; Pathway interactions; Patients; Pattern; Periodontal Diseases; Periodontitis; Periodontium; Phenotype; Phosphorylation; Proteins; Public Health; Recruitment Activity; Research; Role; Scientist; Signal Transduction; TNFSF11 gene; Therapeutic; Tissues; Tumor Necrosis Factor-alpha; United States; Up-Regulation; base; chromatin modification; connective tissue metabolism; cytokine; diabetic; diabetic patient; gene repression; healing; histone modification; pathogen; pre-doctoral; promoter; research study; response; transcription factor

DESCRIPTION (provided by applicant): Chronic inflammatory diseases such as periodontal disease are greatly exacerbated in diabetic patients (Wang and Kaltenboeck, 2010). The mechanism of the acceleration of periodontitis remains unknown, however, diabetes and periodontitis both activate the pro-inflammatory transcription factor NF-?B. Upon stimulation, NF-?B recruits other proteins such as modification enzymes. Modification enzymes alter the chromatin structure via histone modification mechanisms ultimately regulating transcription. In the present study, we will examine histone methylation of gene promoters concomitantly expressed in high glucose conditions (diabetes) and under lipopolysaccharide (LPS) challenge (periodontitis). Microarray gene expression analysis from our preliminary study revealed that periopathic LPS challenge affects three groups of NF-kB target genes corresponding to unique histone methylation signature: (i) immediate-early response genes associated with cell recruitment such as CCL2, CXCL1,and IL-6 which demonstrated active H3K4me3 methylation (ii) late response genes associated with cell activation and defense mechanisms such as IL-1ß, TNF-α, and several defensins that featured repressive H3K9me3 and/or H3K27me3 methylation and (iii) matrix-related genes involved in bone and connective tissue metabolism such as collagens I and III, MMP2 and 9, and RANKL were occupied by both active and repressive trimethylation marks. We propose that long-term inflammation severely alters the methylation state of these periodontal connective tissues which diminishes its ability to function normally and results in chronic periodontitis. We thus hypothesize that in response to periopathic LPS challenge and high glucose conditions, NF-kB avails itself of the histone methylation machinery, resulting in upregulation of pro-inflammatory genes and dysregulation of matrix-related genes, linked to exacerbated periodontitis under diabetic conditions. We have therefore developed a research plan to (1) identify gene expression and epigenetic histone methylation patterns in the aforementioned groups of NF-kB target genes during the progression of periodontitis, (2) to determine the role of NF-κB and chromatin modifications in the exacerbated periodontal phenotype of diabetic animals, and (3) identify the relationship between NF-κB signaling, chromatin structure and histone methylation. Together, these experiments will provide epigenetic information about functional links between diabetes and periodontitis which may result in improvements in therapeutic strategies for periodontitis under diabetic conditions.

描述（由申请人提供）：慢性炎症性疾病（如牙周病）在糖尿病患者中严重加重（Wang和Kaltenboeck，2010）。牙周炎的发病机制尚不清楚，但糖尿病和牙周炎都激活了促炎转录因子NF-？B。刺激后，NF-？B招募其他蛋白质，如修饰酶。修饰酶通过组蛋白修饰机制改变染色质结构，最终调节转录。在本研究中，我们将研究组蛋白甲基化的基因启动子伴随表达在高糖条件下（糖尿病）和脂多糖（LPS）的挑战（牙周炎）。我们初步研究的微阵列基因表达分析显示，围产期LPS攻击影响三组对应于独特组蛋白甲基化特征的NF-κ B靶基因：（i）与细胞募集相关的立即早期应答基因，例如CCL 2、CXCL 1和IL-6，其显示出活性H3 K4 me 3甲基化;（ii）与细胞活化和防御机制相关的晚期应答基因，例如IL-10，TNF-α和几种具有抑制性H3 K9 me 3和/或H3 K27 me 3甲基化的防御素，以及（iii）参与骨和结缔组织代谢的基质相关基因，如胶原蛋白I和III、MMP 2和9以及RANKL，均被活性和抑制性三甲基化标记占据。我们认为，长期炎症严重改变了这些牙周结缔组织的甲基化状态，降低了其正常功能的能力，导致慢性牙周炎。因此，我们假设，在响应于牙周病的LPS挑战和高糖条件下，NF-κ B利用组蛋白甲基化机制，导致促炎基因的上调和基质相关基因的失调，与糖尿病条件下牙周炎的恶化有关。因此，我们制定了一项研究计划，以（1）确定牙周炎进展过程中上述NF-κ B靶基因组的基因表达和表观遗传组蛋白甲基化模式，（2）确定NF-κB和染色质修饰在糖尿病动物牙周表型恶化中的作用，（3）确定NF-κB信号传导、染色质结构和组蛋白甲基化之间的关系。总之，这些实验将提供有关糖尿病和牙周炎之间的功能联系的表观遗传信息，这可能导致糖尿病条件下牙周炎治疗策略的改进。