This proposal details a 5-year training program for the development of an academic career in the pathogenesis of asthma and allergic inflammation. The PI will focus her efforts on acquiring critical skills in molecular biology and mouse models of asthma to become an independent investigator. The PI completed fellowships in Pulmonary and in Allergy and Immunology at Brigham and Women's Hospital, including two years of research on the role of cysteinyl leukotrienes (cys-LTs) as powerful pro-inflammatory mediators. She is now an Instructor in Medicine with plans to continue basic science research under the direction of Dr. Frank Austen (mentor) and Dr. Yoshihide Kanaoka (co-mentor). Dust mite is one of the most significant allergens world-wide and has been linked to asthma pathogenesis. Recent work in Dr. Austen's lab shows that glycans in house dust mite extract elicit robust production of cys-LTs, and that the myeloid C-type lectin receptor, Dectin-2, mediates this process. This work describes a novel mechanism by which allergens can promote inflammation and identifies an important function for this newly-described pattern-recognition receptor. In the proposed plan, we will investigate the role of Dectin-2 signaling, and the subsequent cys-LTs produced, in dendritic cell activation (Aim 1) and in the generation of innate and adaptive pulmonary inflammation (Aim 2) in response to dust mite. The mentor is an eminent scientist in the field with over 50 established trainees and is fully focused on his current laboratory program. The co-mentor is an established molecular biologist who will directly supervise the trainee. In addition, an advisory group includes experts in pattern recognition receptors (Dr. Kobayashi) and eicosanoid biology (Dr. Boyce). Dr. Lambrecht, an expert in mouse models of dendritic cell function in asthma, will consult. The research will take place within the highly collaborative Inflammation and Allergic Diseases Research Section, a source of additional support. Lastly, the institution is committed to providing the necessary resources and training to help the primary investigator establish an independent career.
House dust mite is one of the most significant causes of allergy worldwide, and this allergy is a risk factor for the development of asthma. Studies to determine why this house dust mite is so immunogenic will be helpful to design new therapies for asthma prevention and treatment.
|Lee, Min Jung; Yoshimoto, Eri; Saijo, Shinobu et al. (2016) Phosphoinositide 3-Kinase Î´ Regulates Dectin-2 Signaling and the Generation of Th2 and Th17 Immunity. J Immunol 197:278-87|
|Tjota, Melissa Y; Hrusch, Cara L; Blaine, Kelly M et al. (2014) Signaling through FcRÎ³-associated receptors on dendritic cells drives IL-33-dependent TH2-type responses. J Allergy Clin Immunol 134:706-713.e8|
|Parsons, Matthew W; Li, Li; Wallace, Aaron M et al. (2014) Dectin-2 regulates the effector phase of house dust mite-elicited pulmonary inflammation independently from its role in sensitization. J Immunol 192:1361-71|
|Barrett, Nora A; Boyce, Joshua A (2013) Activation of group 2 innate lymphoid cells: a new role for cysteinyl leukotrienes. J Allergy Clin Immunol 132:214-6|
|Barrett, Nora A; Fernandez, James M; Maekawa, Akiko et al. (2012) Cysteinyl leukotriene 2 receptor on dendritic cells negatively regulates ligand-dependent allergic pulmonary inflammation. J Immunol 189:4556-65|
|Barrett, Nora A; Rahman, Opu M; Fernandez, James M et al. (2011) Dectin-2 mediates Th2 immunity through the generation of cysteinyl leukotrienes. J Exp Med 208:593-604|
|Breslow, Rebecca G; Rao, Jayanti J; Xing, Wei et al. (2010) Inhibition of Th2 adaptive immune responses and pulmonary inflammation by leukocyte Ig-like receptor B4 on dendritic cells. J Immunol 184:1003-13|