Role of alveolar macrophage in omega-3 fatty acid amelioration of silica-triggered autoimmunity

肺泡巨噬细胞在 omega-3 脂肪酸改善二氧化硅引发的自身免疫中的作用

• 批准号: 10817991
• 负责人: James J Pestka
• 金额: $ 3.34万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10817991
• 关键词: Acute; Alveolar; Alveolar Macrophages; Animal Model; Anti-Inflammatory Agents; Applications Grants; Area; Autoantibodies; Autoimmune Diseases; Autoimmunity; Biology; Biomedical Research; CRISPR/Cas technology; Chronic lung disease; Consultations; Data Set; Development; Dietary Fats; Disease; Dose; Environmental Health; Faculty; Fatty Acids; Feedback; Fetal Liver; Gene Expression; Glucocorticoids; Goals; Grant; Health; Inflammation; Inflammatory; Investigation; Lung; Lupus; Macrophage; Manuscripts; Mediating; Mentors; Occupations; Olives - dietary; Omega-3 Fatty Acids; Phase; Postdoctoral Fellow; Preparation; Productivity; Publications; Request for Applications; Research; Research Personnel; Role; Rotation; Schedule; Scientist; Silicon Dioxide; Supplementation; Toxic effect; Training; Writing; autoimmunity checkpoint; career; career networking; collaborative environment; dietary; experimental study; fatty acid supplementation; genetic approach; graduate student; lupus prone mice; meetings; parent grant; prevent; response; skills; symposium; synergism; toxicant; undergraduate student

ABSTRACT This application requests Research Supplement support for Parent Grant ES2R01ES027353 to promote diversity in environmental health-related research, specifically for supporting Dr. Ashley Anderson’s postdoctoral research that will facilitate her advancement into the next phase of her career as an independent and productive environmental health scientist. In this application, we present 1) a summary of the Parent Grant; 2) proposed investigations within the Parent Grant, that enhance research in the grant while staying within scope of its approved Specific Aims; and 3) a customized Training and Mentoring Plan for Dr. Anderson that will provide her with essential skills required for becoming an independent and productive environmental health researcher. The long term goal of the Parent Grant is to understand how toxicant triggering of lupus and other autoimmune diseases can be prevented by skewing cellular lipids by dietary ω-3 fatty acid supplementation. In the Parent Grant, we employ fetal liver-derived alveolar-like macrophages (FLAMs) and lupus-prone mice to determine how the ω-3 DHA suppresses silica-triggered gene expression and autoantibody responses in the lung. Dr. Anderson will enhance these grant goals by exploring DHA’s capacity to synergize with synthetic glucocorticoids (GCs) in suppressing these responses. GCs are routinely prescribed anti-inflammatory treatments for autoimmune diseases like lupus as well as chronic lung diseases; however, prolonged use of GCs at moderate- to-high doses often result in serious adverse health effects due to toxicity. Since ω-3s and GCs have remarkably complementary effects on critical inflammatory and autoimmune checkpoints, dietary ω-3 supplementation might be a practical strategy for reducing GC doses needed for treating environmental-triggered inflammatory and autoimmune diseases. Towards this end, Dr. Anderson will use FLAMs and the lupus-prone mice to uncover ω-3:GC synergies in the following Supplemental Aims: 1.Dissect the underlying mechanisms regulating the synergistic interactions of GCs and ω-3s on inflammatory gene expression in FLAMs; 2.Relate interactive effects between GCs and ω-3s on acute silica-triggered inflammation to suppressed autoantibody responses in the lung. These Supplemental Aims are within the scope of Parent Grant Aims 1,3,4. A central feature of this Research supplement will be Training and Mentoring of Dr. Anderson. As Mentor, Dr. Pestka will provide state-of-the-art training in animal modeling of inflammation/autoimmunity, macrophage biology, and fatty acid and glucocorticoid modes of action. As Co-mentor, Dr. Olive will provide critical training in functional genetic approaches to leverage CRISPR Cas9-mediated editing for targeted hypothesis-driven experiments and unbiased approaches to generate foundational datasets for Dr. Anderson’s career. Key components of the Training and Mentoring Plan include: i)weekly scheduled consultations with mentors, ii) manuscript/grant writing, iii) development of independent research area with moveable datasets for next job; iv) exceptional collaborative environment ; v) opportunities to mentor honors undergraduate/graduate students, and vi)conference participation.

抽象的 本申请请求家长补助金 ES2R01ES027353 的研究补充支持，以促进 环境健康相关研究的多样性，特别是支持阿什利·安德森博士的博士后 研究将有助于她作为一名独立且富有成效的人进入职业生涯的下一阶段 环境健康科学家在本申请中提出了 1) 家长补助金的摘要；2) 家长补助金内的调查，加强补助金的研究，同时保持在其范围内 批准的具体目标；以及 3) 为安德森博士提供的定制培训和指导计划 具备成为独立且富有成效的环境健康研究员所需的基本技能。 家长补助金的长期目标是了解毒物如何引发狼疮和其他自身免疫性疾病 可以通过在母体内补充 ω-3 脂肪酸来改变细胞脂质来预防疾病。 格兰特，我们使用胎儿肝脏来源的肺泡样巨噬细胞（FLAM）和狼疮易感小鼠来确定 ω-3 DHA 如何抑制肺部二氧化硅触发的基因表达和自身抗体反应 安德森将通过探索 DHA 与合成糖皮质激素协同作用的能力来提高这些资助目标 (GC) 抑制这些反应 GC 是常规的抗炎治疗。 自身免疫性疾病，如狼疮以及慢性肺部疾病；然而，长期使用 GC 由于 ω-3 和 GC 的毒性，过高剂量通常会导致严重的健康不良影响。 对关键炎症和自身免疫检查点的补充作用，饮食中补充 ω-3 可能是减少治疗环境引发的炎症所需的 GC 剂量的实用策略 为此，安德森博士将使用 FLAM 和易患狼疮的小鼠来揭示疾病。 ω-3：GC 在以下补充目标中的协同作用： 1.剖析调节 GCs和ω-3s对FLAM中炎症基因表达的协同相互作用；2.相关相互作用效应； GC 和 ω-3 之间对二氧化硅引发的急性炎症抑制肺部自身抗体反应的影响。 这些补充目标属于本研究的核心特征 1、3、4 的范围。 补充内容是安德森博士的培训和指导，作为导师，佩斯特卡博士将提供最先进的技术。 炎症/自身免疫动物模型、巨噬细胞生物学、脂肪酸和糖皮质激素的培训 作为共同导师，奥利弗博士将提供功能遗传方法的关键培训，以利用这些方法。 CRISPR Cas9 介导的编辑，用于有针对性的假设驱动实验和公正的方法 为安德森博士的职业生涯生成基础数据集。 包括：i) 每周与导师进行定期磋商，ii) 手稿/赠款写作，iii) 发展 具有可用于下一项工作的可移动数据集的独立研究领域； iv) 卓越的协作环境； 指导本科生/研究生的机会，以及 vi) 参加会议。