Histone Deacetylase Inhibitors and Inflammatory Bowel Disease

组蛋白脱乙酰酶抑制剂与炎症性肠病

• 批准号: 7806967
• 负责人: Edwin Fulco de Zoeten
• 金额: $ 0.11万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7806967
• 关键词: Acetylation; Acids; Adoptive Transfer; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigens; Antineoplastic Agents; Area; Asthma; Attention; Attenuated; Autoimmunity; Binding; Biological Assay; Boxing; Butyrates; CD4 Positive T Lymphocytes; Catalytic Domain; Cells; Childhood; Chromatin; Clinical; Clinical Management; Clinical Research; Clinical Trials; Colitis; Complementary DNA; Complex; Crohn' s disease; Data; Development; Dimethyl Sulfoxide; Disease; Disease model; Dose; Enzyme-Linked Immunosorbent Assay; Enzymes; Epigenetic Process; Epithelial Cells; Equilibrium; Evaluation; Flow Cytometry; Funding; Future; Genes; Genetic Transcription; Genus Cola; HDAC4 gene; Hepatology; Histidine; Histology; Histone Acetylation; Histone Deacetylase Inhibitor; Histones; Human; IL2RA gene; IL8 gene; IgE; Immune; Immune response; Immune system; Immunohistochemistry; Immunologics; In Vitro; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Injury; Interleukin-12; Interleukin-2; Intestinal Diseases; Intestines; Investigation; Laboratories; Lead; Lupus; Lysine; Mentored Research Scientist Development Award; Mentors; Mesentery; Methods; Modeling; Mucositis; Mus; Mutagenesis; Mutation; Pathogenesis; Physical condensation; Physicians; Population; Prevention; Production; Protein Acetylation; Proteins; Reagent; Regulation; Relative (related person); Research Personnel; Research Training; Role; Scientist; Series; Site; Sodium Dextran Sulfate; Spleen; Staining method; Stains; Structure; T-Lymphocyte; Tail; Testing; Therapeutic; Tissues; Training Programs; Transferase; Trichostatin A; Ulcerative Colitis; Vorinostat; Work; chromatin immunoprecipitation; chromatin protein; cytokine; dosage; drinking water; forkhead protein; gene repression; immunopathology; improved; in vivo; inhibitor/antagonist; interest; lymph nodes; mRNA Expression; mouse model; mutant; prevent; programs; promoter; research study; response; skills; transcription factor; valproate; vector

DESCRIPTION (provided by applicant): This proposal describes a comprehensive training program to transition Dr. de Zoeten from a mentored scientist into an independent investigator in the area of Pediatric Gl and Hepatology. He will focus on the study of the immunopathology of inflammatory bowel disease (IBD), with the ultimate purpose of ameliorating this and other complex intestinal disorders. Over the course of these studies, the PI will acquire laboratory skills, research training, and critical reagents which will enable him to begin work as an independent physician/scientist. Inflammatory bowel disease (IBD) involves dysregulation of mucosal T cells. There is currently much interest in the functions of naturally occurring CD4+CD25+ regulatory T cells (Tregs) - distinguished from other CD4+ cells by baseline expression of CD25 and intracellular expression of FoxpS - as agents to regulate inflammation. Histone deacetylases (HDACs) are enzymes that deacetylate lysine residues and induce transcriptional repression through chromatin condensation. When HDACs are inhibited, lysine residues on histone tails become hyperacetylated, chromatin becomes accessible for transcription factor binding and gene transcription occurs. It is now also recognized that non-chromatin proteins can be regulated by acetylation and de-acetylation. Histone deacetylase inhibitors (HDACi) typically bind the catalytic sites of HDACs, blocking substrate access, thereby allowing histone acetylation and gene transcription. While HDACi are mainly being evaluated as anti-cancer agents, they have also been evaluated in models of inflammation. We plan to utilize these compounds in the treatment of IBD. The proposed studies will assess the effects of HDACi, including Trichostatin A (TsA), Suberolylanilide hyroxamic acid (SAHA) and/or valproate in 3 different models of colitis. We will also use these models to determine which HDACs are involved in colitis, and whether Tregs are critical to the beneficial effects of HDACi on colitis. We have noted that treatment of mice with TsA is associated with FoxpS acetylation and we will therefore evaluate, through mutagenesis of key lysines on Foxp3, if the effects of HDACi is dependent upon acetylation of those sites. Finally, we note multiple HDACs are elevated in activated Tregs and plan to examine the relative importance of these HDACs so as to assess whether future selective HDACi therapy may be warranted. Relevance: The information which will be obtained from this and future investigations will improve our understanding of the immunopathology of IBD, as well as the epigenetic regulation of regulatory T cells, and may enhance the therapy and prevent complications of this disease.

描述（由申请人提供）： 该提案描述了一项综合培训计划，旨在将 de Zoeten 博士从一名受指导的科学家转变为儿科胃肠病学和肝病学领域的独立研究者。他将专注于炎症性肠病（IBD）的免疫病理学研究，最终目的是改善这种疾病和其他复杂的肠道疾病。在这些研究过程中，PI 将获得实验室技能、研究培训和关键试剂，这将使他能够开始作为一名独立的医生/科学家工作。炎症性肠病 (IBD) 涉及粘膜 T 细胞的失调。目前，人们对天然存在的 CD4+CD25+ 调节性 T 细胞 (Treg) 的功能非常感兴趣，该细胞通过 CD25 的基线表达和 FoxpS 的细胞内表达与其他 CD4+ 细胞区分开来，作为调节炎症的药物。组蛋白脱乙酰酶 (HDAC) 是使赖氨酸残基脱乙酰并通过染色质浓缩诱导转录抑制的酶。当 HDAC 受到抑制时，组蛋白尾部的赖氨酸残基变得高度乙酰化，染色质变得易于与转录因子结合并发生基因转录。现在人们还认识到非染色质蛋白可以通过乙酰化和去乙酰化来调节。组蛋白脱乙酰酶抑制剂 (HDACi) 通常结合 HDAC 的催化位点，阻止底物进入，从而允许组蛋白乙酰化和基因转录。虽然 HDACi 主要作为抗癌药物进行评估，但它们也在炎症模型中进行了评估。我们计划利用这些化合物来治疗 IBD。拟议的研究将评估 HDACi（包括 Trichostatin A (TsA)、Suberolylanilide hyroxamic Acid (SAHA) 和/或丙戊酸盐）在 3 种不同结肠炎模型中的作用。我们还将使用这些模型来确定哪些 HDAC 与结肠炎有关，以及 Treg 是否对于 HDACi 对结肠炎的有益作用至关重要。我们注意到，用 TsA 治疗小鼠与 FoxpS 乙酰化有关，因此我们将通过 Foxp3 上关键赖氨酸的诱变来评估 HDACi 的作用是否依赖于这些位点的乙酰化。最后，我们注意到激活的 Tregs 中多个 HDAC 升高，并计划检查这些 HDAC 的相对重要性，以评估未来选择性 HDACi 治疗是否有必要。相关性：从本次研究和未来的研究中获得的信息将提高我们对 IBD 免疫病理学以及调节性 T 细胞表观遗传调控的理解，并可能增强治疗并预防该疾病的并发症。