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

摘要 此申请要求研究补充支持父母补助金ES 2 R 01 ES 027353，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，这将有助于她进入她的职业生涯的下一个阶段，作为一个独立的和富有成效的 环境健康科学家在本申请中，我们提出1）父母补助金的摘要; 2）建议 在父母补助金内进行调查，在补助金范围内加强研究，同时保持在其范围内。 批准的具体目标;和3）为安德森博士定制的培训和指导计划， 具备成为独立和富有成效的环境健康研究人员所需的基本技能。的 家长补助金的长期目标是了解如何有毒触发狼疮和其他自身免疫性疾病 通过膳食ω-3脂肪酸补充剂使细胞脂质偏斜可以预防疾病。在母 格兰特，我们采用胎肝衍生的肺泡样巨噬细胞（FLAM）和狼疮倾向小鼠，以确定 ω-3 DHA如何抑制肺中二氧化硅触发的基因表达和自身抗体反应。博士 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 (GCs)抑制这些反应。GC是常规处方的抗炎治疗， 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在中度- 过高的剂量常常由于毒性而导致严重的不良健康影响。由于ω-3 s和GC具有显着的 对关键炎症和自身免疫检查点的互补作用，膳食ω-3补充剂 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， 和自身免疫性疾病。为此，安德森博士将使用FLAM和狼疮易感小鼠来揭示 ω-3：GC协同作用的补充目的如下：1.解剖调节 GC和ω-3s对FLAMs中炎性基因表达的协同相互作用; 2.相关的相互作用 GC和ω-3s对急性二氧化硅触发的炎症抑制肺部自身抗体反应的影响。 这些补充目标属于母公司赠款目标1、3、4的范围。本研究的一个主要特点是 补充将是安德森博士的培训和指导。作为导师，佩斯卡博士将提供最先进的 炎症/自身免疫、巨噬细胞生物学、脂肪酸和糖皮质激素动物模型的培训 行动方式。作为共同导师，Olive博士将提供功能遗传学方法的关键培训， CRISPR Cas9介导的编辑用于靶向假设驱动的实验和无偏见的方法， 为安德森博士的职业生涯生成基础数据集。培训和指导计划的主要组成部分 包括：i）每周与导师进行定期磋商，ii）撰写手稿/赠款，iii）制定 独立的研究领域，为下一个工作提供可移动的数据集; iv）特殊的协作环境; v） 指导荣誉本科生/研究生的机会，以及vi）会议参与。

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.