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Principal Investigator: Timothy Tun Hla
Organization: BOSTON CHILDREN'S HOSPITAL
Fiscal Year: 2024
Award: $475,344
Funding agency: National Eye Institute
PROJECT SUMMARY
Retinal vascular dysfunction leads to visual impairment and loss of vision, a phenomenon that occurs in
retinopathy of prematurity (ROP), diabetic retinopathy (DR) and neovascular age-related macular degeneration
(AMD). Injury of the retinal endothelial cell (REC) initiates a series of pathogenetic events that ultimately lead
to accelerated progression of retinal diseases. How REC injury leads to transcriptional changes that determine
whether the retinal vascular function is restored or leads to pathological changes is not known. Sphingosine
1-phosphate (S1P), a blood-borne lipid mediator that signals via G protein-coupled S1P receptors (S1PR1-5).
The applicant’s laboratory discovered the first S1PR and worked out its functional roles in vascular barrier
maintenance, development/ maturation, anti-inflammatory processes, cell survival and endothelial/ pericyte
interactions. Although two FDA-approved S1PR-targeted drugs are efficacious in the treatment of multiple
sclerosis, retinal blistering and macular edema are dose-limiting adverse effects due to the impairment of
retinal barriers. We recently showed that S1PR signaling suppresses vascular endothelial growth factor
(VEGF)-induced AP-1 transcription factor activity and permits Norrin/Wnt/ß-catenin-dependent REC gene
expression, thus leading to retinal REC specialization. Among the AP-1 factors, JunB protein expression is
most prominently regulated by S1PR signaling, an event needed for optimal vascular network expansion and
formation of deep retinal vascular plexus. The central hypothesis of the proposal is that REC S1PR signaling
establishes JunB transcription factor gradients and permits the REC organotypic specialization mechanisms.
In this manner, attenuated S1PR signaling axis drives poorly functional retinal vascular network and
vasoproliferative ROP. In this proposal, the first specific aim will elucidate mechanisms and consequences of
S1PR sculpting of JunB transcription factor gradients in REC. Second, how S1PR signaling in the REC
promotes organotypic specialization by enabling efficient Norrin/Wnt/ß-catenin-dependent signal transduction
and gene expression will be conducted. Specific focus will be on omega-3 fatty acid transporter (MFSD2A) and
iron transporter (TFRC). The relevance of these mechanisms in the mouse models of ROP will be addressed
in specific aim 3. These studies are anticipated to enhance our understanding of basic mechanisms of retinal
vascular development, specialization and disease in the retina and ultimately lead to approaches that tame
retinal disorders by targeting the S1P lipid signaling axis and to provide S1PR inhibitors with fewer side effects.
Terms: <0-11 years old><AP-1><AP-1 Enhancer-Binding Protein><AP1><AP1 protein><Abscission><Acceleration><Activator Protein-1><Address><Adventitial Cell><Adverse effects><Age related macular degeneration><Age-Related Maculopathy><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Attenuated><Basal Transcription Factor><Basal transcription factor genes><Beta Cadherin-Associated Protein><Beta-1 Catenin><Bleb><Blindness><Blister><Blood><Blood Reticuloendothelial System><Blood Vessels><Blood-Retinal Barrier><Brain><Brain Nervous System><Bulla><Bullous Lesion><CD71><CUL-2><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Cell Survival><Cell Viability><Cells><Cellular biology><Cellular injury><Chaperone><Child><Child Youth><Childhood><Children (0-21)><Chromatin><Code><Coding System><Coupled><Development><Diabetes Mellitus><Diabetic Retinopathy><Diminished Vision><Disciform macular degeneration><Disciform senile macular retinal degeneration><Disease><Disorder><Dose Limiting><Drug Targeting><Dysfunction><Edg Receptors><Elderly><Encephalon><Endothelial Cells><Endothelium><Engineering><Enhancer-Binding Protein AP1><Environment><Event><Excision><Exhibits><Extirpation><Exudative AMD><Exudative age-related macular degeneration><Eye><Eyeball><FDA approved><Fe element><Functional disorder><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><G-Proteins><GPCR><GTP-Binding Proteins><GTP-Regulatory Proteins><Gene Deletion><Gene Expression><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Generalized Growth><Genes><Genetic><Genetic Transcription><Growth><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><Health><Hypertension><Hypoxia><Hypoxic><Impairment><Inflammation><Inflammatory Response><Injury><Intracellular Communication and Signaling><Iron><Laboratories><Lead><Ligands><Lipids><Low Vision><MS treatment><Maintenance><Mediating><Medulla Spinalis><Metabolic><Metabolic stress><Modeling><Molecular><Molecular Chaperones><Neovascular AMD><Neovascular age-related macular degeneration><Nutrient><Omega-3 Fatty Acids><Omega-3 PUFA><Omega-3 Polyunsaturated Fatty Acid><Omega3><Organ><Oxygen Deficiency><PRO2286><Partial Sight><Pathologic><Pathology><Pathway interactions><Patients><Pb element><Pericapillary Cell><Pericytes><Perivascular Cell><Phase><Phenotype><Physiopathology><Procedures><Process><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Reduced Vision><Regulation><Removal><Research><Retina><Retinal Blood Vessels><Retinal Diseases><Retinal Disorder><Retinal Vessels><Retinopathy of Prematurity><Retrolental Fibroplasia><Role><Rouget Cells><S1P Receptor><Series><Sight><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Sphingosine-1-Phosphate Receptor><Spinal Cord><Subnormal Vision><Surgical Removal><TFR gene><TFR protein><TFR1><TFRC><TFRC gene><TRFR><Testicles><Testing><Testis><Therapeutic><Tissue Growth><Transcription><Transcription Activation><Transcription Factor AP-1><Transcription Factor Proto-Oncogene><Transcription Regulation><Transcription factor genes><Transcriptional Activation><Transcriptional Control><Transcriptional Regulation><Transferrin Receptor><Transferrin Receptor 1><VEGF><VEGFs><Vascular Diseases><Vascular Disorder><Vascular Endothelial Cell><Vascular Endothelial Growth Factors><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Vascular Proliferation><Vesication><Vision><Visual impairment><Wet AMD><Work><advanced age><age dependent macular degeneration><age induced macular degeneration><age related macular disease><age related macular dystrophy><attenuate><attenuates><beta catenin><biological signal transduction><blood vessel disorder><cell biology><cell culture><cell cultures><cell damage><cell injury><cellular damage><damage to cells><developmental><diabetes><experiment><experimental research><experimental study><experiments><gene deletion mutation><geriatric><global gene expression><global transcription profile><heavy metal Pb><heavy metal lead><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><inhibitor><injuries><injury to cells><insight><kids><lipid mediator><loss of function><macular edema><mouse model><multiple sclerosis therapy><multiple sclerosis treatment><murine model><n-3 Fatty Acids><neonatal mice><nerve cell death><nerve cell loss><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal cell death><neuronal cell loss><neuronal death><neuronal loss><novel><omega-3><ontogeny><pathophysiology><pathway><pediatric><permissiveness><pharmacologic><premature><premature retinopathy><prematurity><programs><protein expression><resection><retina blood vessel structure><retina disease><retina disorder><retinopathy><senile macular disease><senior citizen><side effect><social role><sphingosine 1-phosphate><transcription factor><transcriptome><transcriptome sequencing><transcriptomic sequencing><transcytosis><vascular><vascular bed><vascular dysfunction><vasculopathy><vesicle transport><vesicular transport><vision impairment><vision loss><visual function><visual loss><visually impaired><wet form of AMD><youngster><β-catenin><ω-3 fatty acids>