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

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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.