Regulating Cathelicidin Expression for Disease Therapy

调节导管素表达以治疗疾病

• 批准号: 8049149
• 负责人: Adrian Friedrich Gombart
• 金额: $ 35.14万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-15 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049149
• 关键词: Achievement; Antibiotic Resistance; Atopic Dermatitis; Automobile Driving; Bacteria; Binding; Biological; CCAAT-Enhancer-Binding Proteins; CREB1 gene; Cebidae; Cholecalciferol; Clinical; Defensins; Development; Disease; Epithelial; Epithelial Cells; Family; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Transcription; Goals; Health; Hematopoietic; Host Defense; Human; Immune; In Vitro; Infection; Inflammation; Investigation; Knowledge; Lead; Mammals; Mediating; Microbe; Molecular; Myelogenous; Myeloid Cells; Pharmaceutical Preparations; Primates; Process; Prosimii; Regulation; Research; Retinoids; Sepsis; Signal Pathway; Steroids; Testing; Therapeutic; Therapeutic Uses; Thyroid Hormone Receptor; Tissues; Transcriptional Regulation; Transgenic Mice; Vitamin D; Vitamins; activating transcription factor; antimicrobial; antimicrobial peptide; antimicrobial peptide LL-37; cathelicidin; cell type; driving force; human disease; in vivo; in vivo Model; insight; interest; microbial; mouse model; neutrophil; novel; pathogen; promoter; response; small molecule; transcription factor

DESCRIPTION (provided by applicant): Infections by antibiotic resistant bacteria and the potential for sepsis are a major health concern. Antimicrobial peptides (AMPs) like cathelicidins (CAMP) and defensins are generating considerable interest for therapeutic use as potential bactericidals, anti-LPS drugs and modulators of inflammation, and other potential uses. However, the mechanisms governing CAMP expression are largely unknown. The central hypothesis driving the proposed research is that transcription factors (TFs) from the CCAAT/enhancer binding protein (C/EBP), ETS/PU.1, CREB/ATF and the steroid/thyroid hormone receptor families control constitutive and inducible expression of CAMP in hematopoietic and epithelial tissues. We propose an investigation directed towards achieving 3 Specific Aims: [1] Identify the TFs in myeloid and epithelial cells that regulate CAMP gene transcription; [2a] Determine extent of vitamin DS-mediated induction of CAMP in various human cell types and atopic dermatitis; [2b] Identify mechanism of synergistic activation of human CAMP gene expression by retinoids and vitamin D3; [2c] Discover novel small molecules that regulate CAMP gene expression; [3] Elucidate the biological importance and potential therapeutic benefits of vitamin D3 regulation of CAMP gene expression. Specific Aims 1 and 2 will generate a comprehensive assessment of the transcriptional regulation of the CAMP gene in the myeloid and epithelial compartments and identify additional compounds that either alone or in combination with vitamin D3 may prove therapeutically useful. Specific Aim 3 will characterize the evolutionary and biological importance of antimicrobial gene regulation by vitamin D and will use parallel in vitro and in vivo mouse models that exploit a powerful genetic approach to critically examine how vitamin D3 regulates expression of CAMP in response to microbial invasion or challenge with pathogen-derived molecules. Achievement of these specific aims will provide a comprehensive knowledge of the transcriptional regulation of the CAMP gene and demonstrate the biological importance of vitamin D3-mediated regulation of antimicrobial peptides. This knowledge will lead to the development of approaches for extrinsically manipulating endogenous CAMP expression for systemic and localized therapeutic benefit of human diseases.

描述（由申请人提供）：抗生素耐药菌感染和败血症的可能性是一个主要的健康问题。抗菌肽（AMP），如凯萨林菌素（CAMP）和防御素，作为潜在的杀菌剂、抗脂多糖药物和炎症调节剂以及其他潜在用途，在治疗用途方面引起了相当大的兴趣。然而，CAMP表达的调控机制在很大程度上是未知的。推动这项拟议研究的中心假设是，来自CCAAT/增强子结合蛋白（C/EBP）、ETS/PU.1、CREB/ATF和类固醇/甲状腺激素受体家族的转录因子（TF）控制CAMP在造血和上皮组织中的组成型和诱导型表达。我们提出了一项旨在实现3个特定目的的研究：[1]鉴定髓样和上皮细胞中调节CAMP基因转录的TF; [2a]确定维生素DS介导的CAMP诱导在各种人类细胞类型和特应性皮炎中的程度; [2b]鉴定类维生素A和维生素D3协同激活人类CAMP基因表达的机制; [2c]确定维生素D3对人类CAMP基因表达的影响。[2c]发现调节CAMP基因表达的新型小分子; [3]阐明维生素D3调节CAMP基因表达的生物学重要性和潜在治疗益处。具体目标1和2将产生对骨髓和上皮隔室中CAMP基因的转录调控的全面评估，并鉴定单独或与维生素D3组合可能证明治疗有用的其他化合物。具体目标3将表征维生素D对抗菌基因调控的进化和生物学重要性，并将使用平行的体外和体内小鼠模型，这些模型利用强大的遗传方法来严格检查维生素D3如何调节CAMP的表达，以应对微生物入侵或病原体衍生分子的挑战。这些具体目标的实现将提供一个全面的知识的CAMP基因的转录调控，并证明维生素D3介导的抗菌肽的调节的生物学重要性。这些知识将导致开发外部操纵内源性CAMP表达的方法，以获得人类疾病的系统性和局部治疗益处。

项目成果

The vitamin D-antimicrobial peptide pathway and its role in protection against infection.

• DOI: 10.2217/fmb.09.87
• 发表时间: 2009-11
• 期刊: Future microbiology
• 影响因子: 3.1
• 作者: Gombart AF

Low plasma level of cathelicidin antimicrobial peptide (hCAP18) predicts increased infectious disease mortality in patients undergoing hemodialysis.

• DOI: 10.1086/596314
• 发表时间: 2009-02-15
• 期刊: Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
• 作者: Gombart AF;Bhan I;Borregaard N;Tamez H;Camargo CA Jr;Koeffler HP;Thadhani R
• 通讯作者: Thadhani R

Regulation of antimicrobial peptide gene expression by nutrients and by-products of microbial metabolism.

• DOI: 10.1007/s00394-012-0415-4
• 发表时间: 2012-12
• 期刊: European journal of nutrition
• 影响因子: 5
• 作者: Campbell Y;Fantacone ML;Gombart AF
• 通讯作者: Gombart AF

Regulation of the human cathelicidin antimicrobial peptide gene by 1α,25-dihydroxyvitamin D3 in primary immune cells.

• DOI: 10.1016/j.jsbmb.2014.02.004
• 发表时间: 2014-09
• 期刊: JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
• 影响因子: 4.1
• 作者: Lowry, Malcolm B.;Guo, Chunxiao;Borregaard, Niels;Gombart, Adrian F.
• 通讯作者: Gombart, Adrian F.

Exaptation of an ancient Alu short interspersed element provides a highly conserved vitamin D-mediated innate immune response in humans and primates.

• DOI: 10.1186/1471-2164-10-321
• 发表时间: 2009-07-16
• 期刊: BMC genomics
• 影响因子: 4.4
• 作者: Gombart AF;Saito T;Koeffler HP
• 通讯作者: Koeffler HP