NIDCR Individual Predoctoral Scientist Fellowship

NIDCR 个人博士前科学家奖学金

• 批准号: 8875469
• 负责人: Marybeth Francis
• 金额: $ 4.89万
• 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/8875469
• 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; 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 methylation; histone modification; methylation pattern; 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-κB 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（由适用提供）：糖尿病患者中的慢性炎症性疾病（例如牙周疾病）加剧了（Wang and Kaltenboeck，2010年）。但是，牙周炎加速的机制仍然未知，但是，糖尿病和牙周炎都激活了促炎性转录因子NF-B。刺激后，NF-κB募集其他蛋白质，例如修饰酶。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，我们将检查在高葡萄糖条件（糖尿病）和脂多糖（LPS）挑战（牙周炎）下同时表达的基因启动子的组蛋白甲基化。从我们的初步研究中的微阵列基因表达分析表明，周期性LPS挑战影响与独特的组蛋白甲基化特征相对应的三组NF-KB靶基因：（i）与CCL2，CCL2，CXCL1和IL-6相关的细胞募集的立即反应基因，这些基因与CCL2，CXCL1和IL-6相关，这些基因与活性H3K4ME3甲基化的机制相关（II）属性（II）属性（II），II）（II）属性（II）属性（II），这是II）。 TNF-α以及几种具有反射性H3K9ME3和/或H3K27ME3甲基化以及（III）基质相关基因参与骨骼和结缔组织代谢的基因，例如胶原I和III和III，MMP2和9，RANKL均由活跃和反射的Trimethylative Mark占用。我们建议长期炎症严重改变了这些牙周连接的组织的甲基化状态，从而降低了其正常功能并导致慢性牙周炎。因此，我们假设，在应对周期性LPS挑战和高葡萄糖条件下，NF-KB AVALIL本身是组蛋白甲基化机制，从而导致促炎基因的上调和基质相关基因的失调，并与患病的牙周炎息息相关。因此，我们已经制定了一项研究计划，以（1）在牙周炎进展过程中鉴定NF-KB靶基因的近似基因组中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的牙周炎表型中的大量牙周炎和（3）NFRESTICT and（3）甲基甲基之间的关系中的作用。总之，这些实验将提供有关糖尿病和牙周炎之间功能联系的表观遗传信息，这可能会改善糖尿病疾病下牙周炎的治疗策略。