Investigation of RASopathy variants and Raf and Actin-Myosin regulation

This proposal aims to discover insights into how pathogenic, RASopathy-associated genetic variants of human BRAF and RAF1 genes alter Raf protein and the Actin-Myosin cytoskeleton. Our work in Caenorhabditis elegans produced a collection of strains with Raf variants modeled on those found in human the RASopathy disorders Noonan syndrome and Cardiofaciocutaneous syndrome. For this project, we use C. elegans as a robust model where Raf protein localization, the molecular and cellular effects of Raf signaling, and proteins of the Actin-Myosin cytoskeleton are all easily visualized in living animals. Our long term goal is to identify new promising molecular targets for the development of drugs that inhibit Raf kinase signaling. The overall objectives for this project are to (i) assess the subcellular localization, protein levels, and kinase activation of Raf in animals carrying RASopathy variants, and (ii) test the effect of hyperactive Raf on Actin-Myosin contractility and cytoskeleton protein organization. Our central hypothesis is that different RASopathy genetic variants may produce distinct consequences to Raf protein localization, levels, and activity, yet they may share a common effect in altering the Actin-Myosin cytoskeleton. The rationale for this project is that identifying novel cellular targets of Raf signaling will inform new strategies of drug design and discovery. Project Number: 1R03HD121999-01 | Fiscal Year: 2026 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: Claire de la Cova | Institution: UNIVERSITY OF WISCONSIN MILWAUKEE, MILWAUKEE, WI | Award Amount: $144,064 | Activity Code: R03 | Study Section: Cell Structure and Function 1 Study Section[CSF1] View on NIH RePORTER: https://reporter.nih.gov/project-details/11354817