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Assessing how ocular surface nerves, immune cells, and epithelial cells communicate to encourage neuro-immune homeostasis

评估眼表神经、免疫细胞和上皮细胞如何沟通以促进神经免疫稳态

基本信息

批准号：
10595234
负责人：
Daniel H Kaplan
金额：
$ 167.85万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-30 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10595234
关键词：
ATAC-seq Address Affect Afferent Neurons Anatomy Antibodies Architecture Axon Back Binding Proteins Bioinformatics Cells Colon Communication Cornea Corneal Diseases Data Data Set Databases Deposition Dermatology Designer Drugs Development Disease Disease model Dry Eye Syndromes Environment Epigenetic Process Epithelial Epithelial Cells Esthesia Eye Flow Cytometry Fostering Future Ganglia Gastrointestinal tract structure Gene Expression Genetic Goals Graft Rejection Grant Hand Health Herpesvirus 1 Homeostasis Human Imaging Techniques Immune Immunohistochemistry Immunology Infiltration Interdisciplinary Study Intestines Keratitis Keratopathy Knowledge Label Lead Link Location Machine Learning Mass Spectrum Analysis Mediating Membrane Microbiology Modeling Molecular Morphology Mus Nature Nerve Neuroglia Neuroimmune Neurology Neurons Neurotransmitters Ophthalmology Pain Pathologic Pathway interactions Pattern Play Population Process Property Proteins Proteomics Records Regulation Research Role Sensory Shotguns Skin Stimulus Structure Structure of superior cervical ganglion System Technology Tissues Transgenic Mice Vascular Endothelial Growth Factors Viral Wheat Germ Agglutinins Work afferent nerve aqueous base cell type chemokine conjunctiva cytokine design designer receptors exclusively activated by designer drugs gain of function immune checkpoint in vivo large datasets member nerve supply neuroimmunology neuron loss neurotrophic factor novel ocular surface prevent programs protein expression proteomic signature public database receptor recruit relating to nervous system response single-cell RNA sequencing small molecule transcriptomics web portal

项目摘要

PROJECT SUMMARY The nature and function of ocular surface nerves play a critical role in maintaining ocular surface health while preventing disease. Disruption of ocular surface sensory nerves can lead to blinding keratitis, graft rejection, dry eye disease, and ocular surface pain. The advent of “-omics” studies have provided a platform to understand how ocular surface nerves participate in the broader context of ocular health and disease. Here, we outline a proposal that will create large datasets detailing the nature of ocular surface innervation. We will take a systems-level approach towards analyzing our data using bioinformatics and machine learning platforms, so that we can gain a practical understanding of the ocular surface environment during health and disease. Specifically, this proposal will address how ocular surface nerves, epithelial cells, and immune cells interact. We have recruited a multidisciplinary research team that consists experts in ophthalmology, neuroimmunology, neurology, proteomics, systems immunology, and bioinformatics. With this team, we plan to comprehensively analyze all three levels of research outlined in the RFA, which includes anatomical and morphological characterization, defining cellular and molecular properties of neuronal and non-neuronal cell types, and assessing functional properties of neuronal and non-neuronal cells. Because innervation patterns and functionality changes with disease, we will use multiple ocular surface disease models (viral keratitis and aqueous dry eye disease) to better understand how neurons, epithelial cells, and immune cells affect neuronal functionality and subsequent disease. We will achieve our goal by pursuing four specific aims: 1) We will perform single-cell (sc)-omics on neuonrs and non-neuronal cells of the cornea and ocular surface innervating ganglia. These data will characterize neuronal identities and describe their functionality during disease. Additionally, we will be able to molecularly characterize immune and epithelial cells that influence the functionality of ocular surface afferents during disease. 2) We will use mass spectrometry to analyze the proteomic signatures of the cornea during health and disease. An unbiased shotgun approaches and a targeted approach focusing on neurotrophic factors will be used to identify proteins that influence ocular surface nerve functionality. 3) We will use our imaging techniques and histocytometry to comprehensively analyze the location and morphology of neuronal and non-neuronal cells within the cornea, so that we may be able to make conclusions about how nerves, epithelial, and immune cells interact in close proximity at the ocular surface. 4) We will use DREADD (designer receptor exclusively activated by designer drugs) technology to perturb neuronal sensitivity, so that we can assess how altering neuronal responsiveness to stimuli may affect the ocular surface homeostasis and progress of disease. A systems-level analysis of our observations using machine-learning and bioinformatics will lead to the prediction of novel interaction networks that can be interrogated in future studies. All data will be deposited into a web portal that we will develop.

项目总结