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Eric Parigoris
BME Ph.D. Thesis Proposal Presentation
Date: Tuesday, July 20, 2021
Time: 9:30 – 11:30 AM ET
Link: https://bluejeans.com/528086895/7219
Meeting ID: 528 086 895
Participant passcode: 7219
Committee members:
Shuichi Takayama, Ph.D. (Advisor)
YongTae Kim, Ph.D.
David Myers, Ph.D.
Todd Sulchek, Ph.D.
Xueying Zhao, Ph.D
Title:
Exploring the role of radial stretch and fluid shear stress in chronic kidney disease utilizing geometrically-inverted proximal tubule organoids
Abstract:
Chronic kidney disease (CKD), which affects approximately 15% of Americans, causes progressive loss of function of the kidneys and ultimately leads to end stage renal disease. It is characterized by proteinuria, or protein in the urine, and a decreased glomerular filtration rate (GFR). While many have focused on biological considerations of such pathological conditions, mechanical aspects have been largely understudied. Pulsatile fluid flow moving through the proximal tubule generates mechanical stretch and fluid shear stress (FSS); both affect the ability to reabsorb proteins, and lower levels of these forces in diseased states may play a role in decreased reabsorption. However, we lack 3D, high-throughput in vitro models that can apply both forms of mechanical forces, while studying protein uptake. This is largely due to the difficulty in accessing the apical surface, where reabsorption occurs and the surface on which FSS is applied. We recently described a uniform one-drop, one-organoid model that is geometrically-inverted, where the apical side is facing outwards and basolateral side is facing inwards. Because of the ease of apical access, these organoids can be used to study protein reabsorption while experiencing physiological FSS. The goal of this proposal is therefore to generate geometrically-inverted proximal tubule organoids with radial stretch and FSS to have a better understanding of their role in CKD. Our central hypothesis is that both mechanical stretch and FSS will increase megalin expression and activate mechanosensitive ion channels, thereby enhancing albumin reabsorption via receptor-mediated endocytosis; we predict that these mechanical forms of stimulation will aid in protein reabsorption, even in a diseased proteinuric state. In Aim 1, we will establish and characterize geometrically-inverted proximal tubule organoids with natural stretch. In Aim 2, we will expose proximal tubule organoids to FSS to enhance apical endocytosis, giving us a model to further understand how both radial stretch and FSS impact protein reabsorption, even under proteinuric conditions.
