Role of Tissue Resident Macrophages in Conventional Outflow Function

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PROJECT SUMMARY/ABSTRACT Candidate: The candidate, Katy Liu, is an MD/PhD glaucoma fellowship-trained, board-eligible ophthalmologist with a career goal of becoming an independent clinician-scientist. She has a PhD in Cell & Molecular Physiology, and her long-term objective is to better understand the pathobiology of the conventional outflow tract in order to improve treatments and outcomes in patients with glaucoma. Dr. Liu is completing a glaucoma research fellowship and will be promoted to faculty at the Duke Eye Center in July 2020. Career Development Plan: Dr. Liu proposes to investigate the role of tissue resident macrophages in conventional outflow homeostasis, which directly impacts the regulation of intraocular pressure (IOP). The proposed K08 will allow Dr. Liu to expand upon her current scientific knowledge and skills by gaining experience in ocular immunology, aqueous outflow physiology, genetic mouse models, flow cytometry and single-cell RNA sequencing. Dr. Liu will obtain formal didactics in ocular immunology, mouse genetics, biostatistics and responsible conduct of research. She will attend individual meetings with co-mentors to discuss career development, departmental seminars and faculty development workshops. Dr. Liu will regularly attend national meetings to discuss and present ongoing research, and submit her work for publication. Environment: The mentorship team consists of renowned experts in conventional outflow physiology and ocular immunology who are ideal to advise the candidate on her research. The Duke Eye Center is ideal for Dr. Liu with specific strengths in its Glaucoma research program and the Center for Ocular Immunology. She will also benefit from the world-class research and clinical faculty at the Duke Eye Center. Finally, the mentorship team and institution are fully committed to prepare Dr. Liu for independence as an R01-funded scientist. Research: Although immune regulators such as TGF-beta, corticosteroids and prostaglandin analogues are known to alter conventional outflow function, the role of the native immune system in conventional outflow homeostasis is poorly understood. This proposal is designed to test the hypothesis that tissue resident macrophages function in IOP regulation by altering extracellular matrix (ECM) homeostasis in the conventional outflow tract. In Aim 1, macrophages in the outflow tract will be characterized by lineage tracing and their functional effect measured by IOP and outflow facility following pharmacologic depletion or genetic deletion of macrophages. Aim 2 will assess changes to the ECM of the juxtacanalicular trabecular meshwork, the region of greatest outflow resistance generation in the conventional outflow tract, with macrophage deletion by measuring biomechanical stiffness and analyzing ECM components. Aim 2 will also reveal the TM macrophage-specific transcriptome which we will correlate with its functional role in the conventional outflow tract. This project will provide a better understanding of macrophage function in IOP homeostasis, which will influence future therapeutic strategies for glaucoma and serve as the foundation for a future R01 grant.