Project Grant RF1NS137467

BRAIN LYMPHATIC ACTIVATION FOR CRANIOSYNOSTOSIS AND ALZHEIMER'S DISEASE - PROJECT SUMMARY/ABSTRACT THE BRAIN'S LYMPHATIC SYSTEM IS COMPOSED OF GLIA-LYMPHATIC (GLYMPHATIC) AND MENINGEAL LYMPHATIC BRANCHES. THE GLYMPHATIC BRANCH, WHICH IS LOCATED IN THE BRAIN PARENCHYMA, TRANSPORTS CEREBROSPINAL FLUID (CSF) VIA PERIVASCULAR SPACES (PVS) TO CLEAR NEUROTOXIC MOLECULES. IT FUNCTIONALLY CONNECTS WITH THE BRAIN'S SURFACE-LOCATED MENINGEAL LYMPHATIC VASCULATURE FOR CSF DRAINAGE. WHILE BRAIN LYMPHATIC IMPAIRMENT HAS RECENTLY BEEN LINKED WITH NEUROLOGICAL DISORDERS LIKE ALZHEIMER'S DISEASE (AD), TRAUMATIC BRAIN INJURY (TBI), AND CRANIOSYNOSTOSIS, THE REGULATORY MECHANISMS FOR BRAIN LYMPHATIC REJUVENATION ARE LARGELY UNKNOWN. THE GOAL OF THIS PROPOSAL IS TO ESTABLISH MECHANISMS REJUVENATING BRAIN LYMPHATICS AND EXPLOIT BRAIN LYMPHATIC ACTIVATION AS A NEW THERAPEUTIC STRATEGY FOR CRANIOSYNOSTOSIS AND AD. THE SCIENTIFIC PREMISE IS BASED ON OUR RECENTLY PUBLISHED (CELL, 2021, PMID: 33417861) AND UNPUBLISHED DATA (CELL STEM CELL 2023 IN REVISION). SPECIFICALLY, WE ESTABLISHED THE FIRST ANIMAL MODEL (TWIST1+/-) OF NEUROLOGICAL DEFECTS IN CRANIOSYNOSTOSIS AND IDENTIFIED MENINGEAL LYMPHATIC VESSEL (MLV) DEFECT AS A KEY DRIVING FACTOR FOR THESE COGNITIVE DEFECTS. WE ALSO DEVELOPED A MESENCHYMAL STEM CELL (MSC)-BASED SUTURE REGENERATION APPROACH. USING THIS APPROACH, WE SUCCESSFULLY RESCUED NEUROLOGICAL DEFECTS BY REJUVENATING BRAIN LYMPHATIC FUNCTIONS IN TWIST1+/- MICE, THE WELL-ESTABLISHED MODEL FOR SAETHRE-CHOTZEN SYNDROME WITH CRANIOSYNOSTOSIS. OUR DISCOVERY OF BRAIN LYMPHATIC REJUVENATION IN REGENERATION CRANIOSYNOSTOSIS MICE AFFORDS NOT ONLY A NEW THERAPEUTIC STRATEGY FOR TREATING CRANIOSYNOSTOSIS, IT ALSO PROVIDES A UNIQUE ANIMAL MODEL TO INVESTIGATE REGULATORY MECHANISMS UNDERLYING BRAIN LYMPHATIC REJUVENATION. PRELIMINARY DATA GUIDE US TO HYPOTHESIZE THAT MSC-LEC (LYMPHATIC ENDOTHELIAL CELL) CROSSTALK AND THE REMODELING OF AQP4 (GLYMPHATIC SYSTEM MEDIATOR) IN REGENERATION CRANIOSYNOSTOSIS MICE DRIVE BRAIN LYMPHATIC REJUVENATION, WHICH CAN BE EXPLOITED TO MITIGATE CRANIOSYNOSTOSIS AND AD. OVERALL, BUILDING UPON OUR PUBLISHED DISCOVERIES, THE COMPLETION OF PROPOSED STUDIES WILL ADVANCE THE FIELD BY DEVELOPING STEM CELL-MEDIATED TREATMENTS OF CRANIOSYNOSTOSIS, FILLING IN MISSING MECHANISTIC KNOWLEDGE OF MENINGEAL LYMPHATIC REJUVENATION, AND VALIDATING VEGF-C/AQP4 AS POTENTIAL THERAPEUTIC TARGETS FOR CRANIOSYNOSTOSIS AND AD.