Stress sensing by polycystin proteins

The National Institute of General Medical Sciences awarded Loyola University of Chicago $452,051 on April 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to conduct research on stress sensing by polycystin proteins.

The work maps and mechanistically determines the stress signaling and calcium-dependent pathway of polycystin 2 (PC2), an ER-localized calcium channel. Three research themes address: identification of the plasma membrane receptor that detects cell stress (excessive stretch or osmotic stimuli) and relays it to PC2, with focus on polycystin 1 as a candidate; characterization of calcium signaling encoded by PC2 using direct ER-stress stimuli, employing genetically encoded calcium tools, super-resolution microscopy, and electrophysiology; and identification of downstream signaling pathways dependent on PC2-calcium signaling through unbiased sequencing and pathway analysis. The research will involve undergraduate summer research students from the Inter American University of Puerto Rico alongside the Kuo Laboratory at Loyola University Chicago.

Performance occurs in Maywood, Illinois, with a period of performance from April 1, 2026, through February 28, 2031. The award is a Project Grant, classified as assistance funding.

Abstract

Stress sensing by polycystin proteins cells must have specialized molecular detectors and signaling pathways to detect and transmit environmental stimuli respond to different cues in the environment. Yet, the actual identity of the molecules that are in the osmotic and stretch sensing pathway(s) and how this is related to intracellular calcium signaling is not understood. Our prior studies on polycystin 2 (PC2), an ER-localized calcium channel is required for cells to differentiate and for cells to adequately sense and respond to stretch or osmotic stimuli. The goal of this proposal is to build upon our prior studies and comprehensively map and mechanistically determine the stress signaling-CA2+ dependent pathway of PC2. We will achieve this by focusing on 3 themes. Theme 1 will address what plasma membrane receptor detects a cell stress (in this case defined as an excessive cell stretch or osmotic stimuli) and relays this stimulus to PC2. We will build on our preliminary data and existing literature pointing to polycystin 1 (PC1), a known partner protein of PC2 having the requisite biophysical properties to detect excessive cell stretch. Theme 2 will address the CA2+ signaling encoded by PC2 by using direct ER-stress stimuli. The KUO lab and collaborators are poised to answer this question due to our expertise in CA2+ signaling, the development and adaptation of new genetically encoded CA2+ tools, incorporation of super-resolution microscopy and electrophysiology. Theme 3 will use our unbiased sequencing DATA3 followed by pathway analysis to carefully identify and mechanistically understand the downstream signaling pathways that are dependent on PC2-CA2+ dependent signaling. Collectively, this proposal, conducted by the KUO laboratory at loyola university chicago alongside undergraduate summer research students from the inter american university of puerto rico will answer a fundamental knowledge GAP in CA2+ signaling and cellular biology and define how polycystin proteins function in stress-signaling pathways.