All ETDs from UAB

Advisory Committee Chair

Bradley K Yoder

Advisory Committee Members

Michal Mrug

Lucas Pozzo-Miller

Chad Steele

John Parant

Document Type

Dissertation

Date of Award

2020

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Primary cilia are small microtubule based appendages present on nearly every cell type in the mammalian body, and are highly conserved from organisms as simple as algae to humans. Cilia function as complex signaling centers integrating a variety of pathways and play critical roles throughout development and in maintaining homeostasis. Mutations to ciliary proteins in humans result in a wide array of diseases termed ciliopathies, which have a broad range of symptoms affecting nearly every organ in the body. Renal primary cilia are present on the apical side of tubular epithelium, where they project into the lumen and are thought to function as sensors of fluid flow. Mutations affecting cilium structure, such as to transition zone proteins like mks-6, or to a variety of ciliary localized proteins such as polycystin-1 (pkd-1) or pkd-2, result in cystic kidney disease (CKD), demonstrating the importance of functional renal cilia. Importantly, this CKD phenotype is exacerbated by kidney injury, leading researchers to believe renal cilia may also play a role in regulating renal injury responses. While renal cilia are of utmost importance in kidney development and homeostasis, recent work has called into question how they may be sensing flow and remains a large question. The majority of studies attempting to determine the function of renal cilia have been performed in vitro, which lack complexity found in the kidney, including differing regions of the nephron, signaling molecules, and other cell types which may arise from outside the kidney. In the following thesis, I will outline a novel intravital imaging method which allows longitudinal in vivo investigation of renal cilia in transgenic mice, as well as a variety of applications it can be used for to gain insights into malicious phenotypes such as CKD. In addition, I show that administration of a common compound used to manipulate the genome in inducible transgenic mice, tamoxifen, may cause renal injury. Lastly, I demonstrate that renal cilia may be responding to changes in tubule flow following kidney injury, and these changes may be necessary for resolution of that injury; mutations to cilia may affect their ability to respond to changes in flow and lead to cystogenesis.

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