Integration of cell signaling by the primary cilium

The National Institute of General Medical Sciences awarded $422,688 to the Regents of the University of California at Riverside on August 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859, Assistance Listing 93.859).

The award funds basic research on cell signaling through the primary cilium, a microtubule-based organelle that functions as the cell's signaling hub. The research addresses how the primary cilium senses environmental signaling cues and transduces them to intracellular pathways governing cell behavior, with application to understanding ciliopathies—diseases arising from cilium dysfunction. The project expands prior work mapping ciliary proteomes across different cell types by investigating two directions: the connection between cilium signaling and mitochondrial function and cellular metabolism, building on discovery of protein translocation from mitochondria to the cilium in response to nutrient status changes; and local translation of specific mRNAs in distinct regions and contexts.

Performance occurs at UC Riverside in Riverside, California. The award period runs from August 1, 2026 through July 31, 2031.

Abstract

Primary cilium, a microtubule-based hair-like organelle, functions as the signaling hub for the cell. The cilium senses signaling cues from the environment and transduces them to intracellular pathways that dictate the cell's behavior. Cilium dysfunction leads to a wide spectrum of human diseases, collectively known as ciliopathies. The diversified roles of cilium are supported by the distinct composition of signaling proteins within the cilia across different tissues. The major challenges in the field are: 1) what are the distinct ciliary protein compositions across different cell types? And 2) how ciliary signaling is communicated to other organelles to coordinate cell responses? Addressing these questions is essential to our understanding of cilium's function and its associated ciliopathies. In the past few years, my lab has endeavored to tackle the first challenge by profiling ciliary proteomes in different cell types and at different signaling conditions. We leveraged a proximity labeling tool and systematically mapped ciliary proteins in cultured fibroblasts and in the developing brain. Our ciliary proteomics revealed striking differences in ciliary components across different cell types in vitro and in vivo. We have already harnessed these results to advance our understanding of hedgehog signaling transduction mechanisms in the cilium. Meanwhile, our cilium proteomic results opened new avenues to decipher the mechanistic connection between the cilium and other organelles and cellular events. In this R35 proposal, we will expand our research into two most intriguing directions: (1) how is cilium signaling connected to mitochondrial function and cellular metabolism? This project builds on our discovery of a remarkable protein translocation from mitochondria to the cilium in response to changes in nutrient status. (2) which mrnas are locally translated in specific regions and distinct stages in the cilia of neural progenitors in the developing brain? This project builds on our in vivo cilium proteomics, which revealed a prominent enrichment of mrna-binding proteins in the cilia. Thus, we will leverage our unique cilium proteomic findings to address the 2ND challenge in the field. We will integrate cutting-edge technologies with rigorous research design to answer the fundamental questions in cilium biology. Upon completion, our study will shed light on how cilia communicate with other organelles; the ciliary mrna profiling will pave the way to our understanding of local protein translation in the cilium in development and disease.