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Principal Investigator: Anne Christine Eichmann
Organization: YALE UNIVERSITY
Fiscal Year: 2024
Award: $548,579
Funding agency: National Institute of Neurological Disorders and Stroke
The objectives of the proposal are to determine, for the first time, how developing meningeal
lymphatic vessels (MLVs) impact neuroimmune communication in early postnatal life, and if MLV-
dependent neuroimmune communication can be harnessed by VEGF-C signaling in young mice
at steady state and in a model of pediatric brain tumor such as medulloblastoma, the most
common tumor affecting children.
Our previous work and preliminary data show that MLVs develop during early postnatal life,
that their growth requires Vascular Endothelial Growth Factor-C (VEGF-C) and the VEGF-C co-
receptor Neuropilin2 (Nrp2), and that enhancing MLV growth enables adaptive immune
responses against glioblastoma in the adult. These findings prompt us to investigate mechanims
how MLV-mediated neuroimmune connection establishes and to characterize the transport of
antigen-presenting cells (APCs) to CNS-collecting lymph nodes (cLNs) and the MLV-dependent
education of T cells in developing cLNs.
Experimental approaches to successfully complete this project include new lymphatic-specific
knockout lines, new procedures of three-dimensional whole-head imaging by light sheet
fluorescence microscopy, and unbiased molecular analysis by mass spectrometry and single cell-
RNA sequencing.
This multidisciplinary study will bring together complementary expertise in the fields of
meningeal lymphatics (Jean-Leon Thomas, Yale), developmental angiogenesis (Anne Eichmann,
Yale), and immunology (Akiko Iwasaki, Yale), with additional advisors in pediatric oncology (Asher
Marks, Director of Yale Pediatric Neuro-Oncology), liquid-chromatography mass spectometry
(Tukiet Lam, Director of Keck MS & Proteomics Resource at Yale), and TCR repertoire analysis
(Le Zhang, Yale Neurology).
We expect to characterize the development of MLV-dependent neuroimmune communication,
to identify Nrp2 as a new mandatory regulator of MLV sprouting, identify APC subpopulation(s)
required for CNS antigen transport into cLNs, and to determine, as a proof of principle, the
potential of VEGF-C-driven MLV growth to promote early T cell education against abnormal CNS
antigens, with perspectives for the treatment of aggressive pediatric brain tumors.
Terms: <0-11 years old><0-4 weeks old><21+ years old><3-D><3-Dimensional><3D><AD dementia><Ablation><Accessory Sinuses><Adult><Adult Glioblastoma><Adult Glioblastoma Multiforme><Adult Human><Affect><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimers Dementia><American><Antigen-Presenting Cells><Antigens><Area><Behavior><Binding><Birth><Body Tissues><Brain><Brain Neoplasia><Brain Neoplasms><Brain Nervous System><Brain Trauma><Brain Tumors><CNS Diseases><CNS Nervous System><CNS Tumor><CNS disorder><CNS neoplasm><Cancerous><Cell Body><Cell Communication and Signaling><Cell Locomotion><Cell Migration><Cell Movement><Cell Signaling><Cells><Cellular Migration><Cellular Motility><Central Nervous System><Central Nervous System Diseases><Central Nervous System Disorders><Central Nervous System Neoplasms><Central Nervous System Tumors><Cerebrospinal Fluid><Checkpoint inhibitor><Child><Child Youth><Childhood><Childhood Brain Neoplasm><Childhood Brain Tumor><Childhood Neoplasm><Childhood Tumor><Children (0-21)><Combined Modality Therapy><Common Neoplasm><Common Tumor><Communication><Cues><Data><Development><Disseminated Sclerosis><Drainage><Drainage procedure><Education><Educational aspects><Encephalon><Environment><FLT4 Ligand><FLT4 Protein><FLT4-L><FMS-Related Tyrosine Kinase 4><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Flt-4><Fluorescence Light Microscopy><Fluorescence Microscopy><Generalized Growth><Genetic><Genetic Models><Glioblastoma><Goals><Grade IV Adult Astrocytic Neoplasm><Grade IV Adult Astrocytic Tumor><Grade IV Adult Astrocytoma><Grade IV Astrocytic Neoplasm><Grade IV Astrocytic Tumor><Grade IV Astrocytoma><Growth><Head><Health system><Image><Imaging Procedures><Imaging Technics><Imaging Techniques><Immune><Immune checkpoint inhibitor><Immune response><Immune system><Immunes><Immunity><Immunological response><Immunology><Injections><Intercellular Fluid><Interstitial Fluids><Intracellular Communication and Signaling><Ischemic Stroke><Knock-out><Knockout><Knowledge><Label><Life><Light><Liquid Chromatography><Lymph Node Reticuloendothelial System><Lymph System><Lymph node proper><Lymphatic><Lymphatic Endothelial Cells><Lymphatic Network><Lymphatic System><Lymphatic System Reticuloendothelial System><Lymphatic nodes><Maintenance><Mass Chromatography><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Mediating><Mediator><Medulloblastoma><Meningeal circuit><Meningeal lymphatic network><Meningeal lymphatic pathway><Meningeal lymphatic system><Meningeal lymphatics><Meninges><Mice><Mice Mammals><Modeling><Molecular><Molecular Analysis><Molecular Interaction><Monitor><Mothers><Multimodal Therapy><Multimodal Treatment><Multiple Sclerosis><Murine><Mus><NRP2 Protein><Nasal Sinuses><Nasal cavity/Paranasal><Nasal cavity/Paranasal sinuses><Neonatal><Nerve Cells><Nerve Unit><Neural Cell><Neuraxis><Neurocyte><Neuroimmune><Neurology><Neurons><Neuropilin-2><Neuropilins><Newborn Infant><Newborns><Npn-2 Protein><PTK Receptors><Paralysis Agitans><Paranasal Sinuses><Parkinson><Parkinson Disease><Parturition><Passive Immunity><Pathology><Pediatric Neoplasm><Pediatric Oncology><Pediatric Tumor><Peripheral><Photoradiation><Play><Primary Parkinsonism><Primary Senile Degenerative Dementia><Procedures><Proteins><Proteomics><Protocol><Protocols documentation><Receptor Protein><Receptor Protein-Tyrosine Kinases><Receptor Tyrosine Kinase Gene><Reporter><Research Resources><Resources><Role><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Sinus><T-Cell Activation><T-Cells><T-Lymphocyte><T-cell receptor repertoire><TCR repertoire><Time><Tissue Growth><Tissues><Tracer><Transmembrane Receptor Protein Tyrosine Kinase><Transmission><Traumatic Brain Injury><Tumor Antigens><Tumor-Associated Antigen><Tyrosine Kinase Linked Receptors><Tyrosine Kinase Receptors><Tyrosine-Protein Kinase Receptor FLT4><Uterus><VEGF-C><VEGFR-3><VEGFR3><Vascular Endothelial Growth Factor C><Vascular Endothelial Growth Factor Receptor-3><Vascular Endothelial Growth Factor Related Protein><Vertebrae><Vertebral><Work><accessory cell><activate T cells><adaptive immune response><adaptive immunity><adulthood><angiogenesis><biological signal transduction><brain tissue><cancer antigens><cell motility><cerebral spinal fluid><combat><combination therapy><combined modality treatment><combined treatment><developmental><draining lymph node><flow cytophotometry><glioblastoma multiforme><host response><imaging><immune check point inhibitor><immune system response><immunogen><immunoresponse><improved><insular sclerosis><kids><lymph channel><lymph gland><lymph nodes><lymph vessel><lymphatic channel><lymphatic drainage><lymphatic vasculature><lymphatic vessel><lymphnodes><macromolecule><meninge><mouse genetics><mouse model><multi-modal therapy><multi-modal treatment><multidisciplinary><murine model><neuro-oncology><neuronal><neurooncology><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><newborn child><newborn children><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><ontogeny><pathogen><pediatric><pediatric brain neoplasm><pediatric brain tumor><pharmacologic><postnatal><primary degenerative dementia><receptor><regional lymph node><scRNA-seq><senile dementia of the Alzheimer type><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><spinal fluid><spine bone structure><spongioblastoma multiforme><synergism><therapeutic target><three dimensional><thymus derived lymphocyte><translation strategy><translational approach><translational strategy><transmission process><traumatic brain damage><tumor><tumor growth><tumor-specific antigen><tumors in children><tumors in the brain><tumors in the central nervous system><womb><youngster>