This K22 Career Development Award Resubmission Application describes my training, my career goals, a plan for career development, and a research project that will launch my independent research program in the study of immune responses and inflammation at mucosal surfaces. My training with Dr. Christopher Hunter and Dr. David Artis at the University of Pennsylvania has given me the technical and intellectual skills required to achieve my goal of becoming an independent investigator at a top-tier academic research institution. My plans for career development will also play a key role as I transition to independence. Training in bioethics, grant-writing, new techniques (mass spectrometry and genome-wide profiling), mentorship, and laboratory management, available to me through institutional resources, the support of collaborators, and a team of mentors, will be crucial. I have also developed a research plan that will form the basis of my independent research program. This project investigates the regulation of innate immune responses in the lung during type 2 immune responses, which promote protective immunity to helminth parasites but can also cause chronic inflammation and pathology during helminth infection and allergy. My postdoctoral work, presented as preliminary data, demonstrates that group 2 innate lymphoid cells (ILC2s), a recently described innate immune cell type that promotes type 2 inflammation in the lung, respond to the bioactive lipid prostaglandin D2 (PGD2) via expression of the receptor CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells). I employ in vitro assays and in vivo infection with Nippostrongylus brasiliensis, a rodent model of hookworm infection and type 2 pulmonary inflammation, to show that type 2 inflammation in the lung in this model is dependent on CRTH2-expressing ILC2s. I also show that ILC2 responses to IL-33, a key cytokine that drives type 2 inflammation, are partially CRTH2-dependent. These data led to the central hypothesis that IL-33 induces PGD2 production that promotes CRTH2-expressing ILC2 responses during type 2 inflammation in the lung. To directly test this, I propose two Specific Aims.
Aim 1 will examine mechanisms by which the PGD2-CRTH2 pathway influences ILC2 responses and helminth-induced type 2 inflammation in the lung, and Aim 2 will test how IL-33-dependent type 2 inflammation may be mediated through the PGD2-CRTH2 pathway, using cutting-edge approaches and complementary analyses of murine and human samples. Insights into how the PGD2-CRTH2 pathway regulates type 2 inflammation will inform the development and effective usage of therapies to treat type 2 inflammatory diseases. Critically, this research project will generate a rich data set that will become the foundation for future NIH funding applications. Together, my training, institutional resources, and the activities supported by this award, including my career development plan and research proposal, will provide me with the tools to build my independent research program and attain my goal of becoming a successful researcher and faculty member at an academic research institution.
Type 2 immune responses protect against helminth infection but can also cause inappropriate inflammation during chronic helminth infection and allergy. This proposal aims to better define how bioactive lipids called prostaglandins influence type 2 responses, which may inform the treatment of type 2 inflammatory diseases.
| Danko, Charles G; Choate, Lauren A; Marks, Brooke A et al. (2018) Dynamic evolution of regulatory element ensembles in primate CD4+ T cells. Nat Ecol Evol 2:537-548 |
| Tait Wojno, Elia D; Beamer, Celine A (2018) Isolation and Identification of Innate Lymphoid Cells (ILCs) for Immunotoxicity Testing. Methods Mol Biol 1803:353-370 |
| Oyesola, Oyebola O; Früh, Simon P; Webb, Lauren M et al. (2018) Cytokines and beyond: Regulation of innate immune responses during helminth infection. Cytokine : |
| Webb, Lauren M; Tait Wojno, Elia D (2017) The role of rare innate immune cells in Type 2 immune activation against parasitic helminths. Parasitology 144:1288-1301 |
| Tait Wojno, Elia D; Artis, David (2016) Emerging concepts and future challenges in innate lymphoid cell biology. J Exp Med 213:2229-2248 |
