Project Grant R01CA325351

The National Institutes of Health Office of the Director awarded The Leland Stanford Junior University $718,129 under the Trans-NIH Research Support program (CFDA 93.310) on September 1, 2026, to engineer and optimize programmable synthetic G protein-coupled receptors (PAGERs) that enable precise, programmatic control of cellular behavior in response to specific molecular cues.

The project addresses the limitations of current synthetic receptor technologies such as CAR-T therapies, which recognize only cell-surface antigens and produce hard-wired responses. The funded work introduces three core innovations: engineering novel PAGER architectures including single-chain designs for in vivo deployment, spatially-localized activity readouts, and "AND-gate" receptors requiring two activating antigens for unprecedented specificity; creating a discovery engine combining computational design with high-throughput directed evolution to develop genetically-encoded antagonists and antigen-binding nanobodies, expanding the platform across the approximately 800-member human GPCR superfamily and diverse soluble and cell-attached antigens; and deploying these tools to dissect GPCR spatial signaling logic by precisely controlling subcellular receptor activation location within living cells and neurons to map distinct signaling networks arising from different organelles, a phenomenon termed "location bias."

Performance occurs at Stanford's Palo Alto, California campus. The period of performance extends from September 1, 2026, through August 31, 2031.