The broad, long-term objectives of this study is to establish conclusive support for exRNA biodistribution, uptake, and function in a wide range of tissues in the living mouse. This is possible due to new genetic technologies and reagents developed in the investigators labs. These include but are not limited to: genetic ablation of the two mouse homologs (SID1/2) of the worm exRNA transporter SIDI;genetic ablation of a host of mouse microRNA exRNAs;and a modular and highly adaptable positive sensor for exRNA activity in live tissues. There is a need to for a concerted effort to develop exRNA tools and reagents to further explore this novel paradigm for understanding human biology and the development of therapeutic intervention strategies. Arguably, mouse models represent the best mammalian models, given the strong parallel to human development and disease, and the increasing abundance of tangible animal resources. However the development of new mouse genetic models requires special skills, sometimes using artisan protocols, and is not cost effective for most labs to adopt. Funding is requested for a mouse genetics core to support three investigators in this U19 proposal, and more broadly, the entire Extracellular RNA Communication Initiative. This Core builds upon an existing highly efficient structure, promoting an economy of scale genetics pipeline integrated into this core.
A better understanding of exRNA effector biodistribution, uptake, and function in target cells will generate tremendous opportunities for identifying novel strategies forthe prognosis, diagnosis, and intervention of human disease.
|Boettcher, Michael; McManus, Michael T (2015) Choosing the Right Tool for the Job: RNAi, TALEN, or CRISPR. Mol Cell 58:575-85|