Molecular mechanisms of akap-mediated signaling compartmentalization and functional diversity

The National Institute of General Medical Sciences awarded the Board of Regents of Nevada System of Higher Education, operating as University of Nevada, Reno, $361,519 on August 1, 2026, under the Biomedical Research and Research Training program (CFDA 93.859) to investigate molecular mechanisms of AKAP-mediated signaling compartmentalization and functional diversity.

Over the next five years, the research will determine how disease-associated anchor protein AKAP11 mediates distinct cell functions using chemical biology techniques to compare AKAP11 complex components across different tissues, stimulation signals, and molecular contexts. The work includes developing a conditional mouse model to establish AKAP expression profiles in specific cell types and generating high-affinity, highly selective targeting peptides designed to concentrate payloads at discrete subcellular locations. The research aims to clarify how disruptions to AKAP signaling complexes contribute to human pathologies and to develop selective interventions that target cell signaling at specific protein complexes, reducing off-target effects compared to conventional broad-acting reagents.

The project runs through March 31, 2031, with place of performance in Reno, Nevada. The award funds a project grant, the standard assistance type under NIGMS's Biomedical Research and Research Training program for investigator-initiated research.

Abstract

The mission of the omar lab is to gain deeper understandings of cell signaling specificity and plasticity in physiologies relevant to human disease, with a particular focus on compartmentalization by protein complexes. Our current efforts focus on understanding the molecular organization mediated by a family of over 60 protein complex nucleators called a-kinase anchoring proteins, or akaps. Each member of this diverse family associates with distinct subcellular machinery and organizes a unique protein complex that matches enzymes with certain substrates and downstream functions. Through these mechanisms, akaps direct signaling proteins to act in specific cell processes and thereby define their roles. Accordingly, disruptions to akap signaling complexes are associated with numerous human pathologies. We are additionally exploiting our findings to develop selective interventions that target cell signaling events at specific protein complexes. Compared to conventional broad-acting reagents, these targeted manipulations are designed to focus their actions at distinct subcellular locations and thereby avoid unintended impacts on off-target cell processes. This approach will enable clearer conclusions regarding the mechanisms of biochemical phenomena and provide a framework for future development of task-selective therapeutics. In the next five years, we aim to determine how the human disease-associated anchor protein AKAP11 mediates seemingly disparate cell functions. This work includes using chemical biology techniques to compare and contrast AKAP11 complex components among different tissues, stimulation signals, and molecular contexts. Additional projects include using a novel conditional mouse model to determine akap expression profiles in specific cell types and developing high-affinity and highly selective targeting peptides that can enrich payloads at AKAP11 complexes. We will accomplish these tasks using an interdisciplinary approach that combines in vivo mouse work, human cell-based systems, validation in resected human tissue samples, and computational workflows. We strive for the highest relevance to human health and therefore prioritize the use of advanced methods that maintain the native molecular environment in our experimental systems. The objectives of the present proposal are to reveal the molecular details that determine AKAP11 function, develop platforms for expanding our impacts on protein complex biology and targeted manipulations, and overall lay the foundation for a long-term high-impact research program.