PROJECT SUMMARY/ABSTRACT Autosomal dominant polycystic kidney disease (ADPKD) is the most commonly inherited kidney disease in the world. It is characterized by large fluid-filled cysts that disrupt kidney function, eventually leading to end stage kidney disease. Previous literature indicates that kidney resident macrophages (KRM) are cyst-associated in human clinical samples and are also found in cystic regions of ADPKD mouse models. KRM accelerate ADPKD as depletion of KRM reduces cystic index and disease progression in mouse models of the disease. Together, these data suggest that targeting KRM may have a clinical impact in patients. Unfortunately, it is currently not feasible to give patients macrophage depleting agents for long periods as these compounds lack specificity, depleting macrophage populations in multiple tissues. This is an important point as macrophages perform critical functions as part of an organism’s innate immune defense. Additionally, ADPKD progresses slowly and patients experience gradual cyst growth and loss of kidney function over several decades of life, thereby requiring long- term intervention. These data highlight that alternative approaches for long-term, kidney-specific resident macrophage depletion are desperately needed. In this application, I propose to study niche filling as a means to achieve long term, kidney specific resident macrophage depletion. This will be achieved by determining the mechanism of KRM niche filling after temporary depletion and through identification of factors, such as Cx3cr1, that we propose are critical for KRM niche filling. The central hypothesis of this proposal is that following temporary depletion, the KRM niche is repopulated via the recruitment and differentiation of bone marrow- derived Ly6chi monocytes and that this process requires Cx3cr1. In Aim 1, I will map out the kinetics and mechanism of KRM niche after temporary depletion in a mouse model of ADPKD. In Aim 2, I will test if loss of Cx3cr1 in monocytes is able to delay KRM niche filling and the progression of cystic disease. My long-term goal is to understand the mechanism of KRM niche filling and translationally apply KRM-centric findings to clinical cases of ADPKD.