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Immunomodulatory ligand B7-1 targets p75 neurotrophin receptor in neurodegeneration

免疫调节配体 B7-1 在神经变性中靶向 p75 神经营养蛋白受体

基本信息

批准号：
10660332
负责人：
BARBARA L HEMPSTEAD
金额：
$ 234.55万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660332
关键词：
Acute Address Adult Affect Affinity Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Animals Anti-Inflammatory Agents Antibodies Antigen-Presenting Cells Atrophic Binding Biochemical Biological Biophysics Blocking Antibodies Brain-Derived Neurotrophic Factor CD28 gene CD80 Antigens CD80 gene CTLA4 gene Cell Surface Proteins Cell surface Cells Central Nervous System Diseases Complex DLG4 gene Data Dendritic Spines Deterioration Dorsal Effectiveness Epitopes Equilibrium Evaluation Exhibits Extracellular Domain FDA approved Goals Hippocampus Human IDEC-114 Monoclonal Antibody Imaging Device Immune Impairment In Vitro Infiltration Inflammation Inflammatory Injections Injury Knock-in Mouse Lead Ligands Macrophage Mammals Maps Memory Microglia Microtubules Modeling Monoclonal Antibodies Morphology Mus NGFR Protein Nerve Degeneration Nerve Growth Factor Receptors Neurodegenerative Disorders Neuroglia Neurons Pharmaceutical Preparations Phenotype Population Prevention Primates Process Proteins Reagent Rest Retrieval Role Secondary to Signal Transduction Specificity Stroke Surface Synapses Techniques Testing Therapeutic Time Traumatic Brain Injury Tumor Necrosis Factor Receptor Validation Vertebral column aging brain basal forebrain cholinergic neurons behavioral impairment behavioral study biophysical properties brain-derived neurotrophic factor precursor cytokine density hippocampal pyramidal neuron humanized mouse imaging study immunoregulation in vitro testing in vivo insight member mouse model nervous system disorder neuroinflammation new therapeutic target novel postsynaptic pre-clinical prevent protein protein interaction receptor response therapeutic protein tool transcriptional coactivator p75

项目摘要

The aging brain is characterized by a slow deterioration of homeostatic balance between pro- and anti-inflam- matory cytokines, resulting in a proinflammatory state. Resident CNS immune cells are normally present in a resting state, but exhibit heightened vulnerability to secondary insults with aging, leading to a phenotypic shift in cell surface marker expression and cytokine release that contribute to the proinflammatory state. The functional contributions of interactions between cell surface proteins of neurons and immune cells have not been fully addressed. Using an unbiased protein-protein interaction screen, we determined that the immunomodulatory ligand B7-1 (CD80) interacts with the p75 neurotrophin receptor (p75). Importantly, the B7-1:p75 interaction is of recent evolutionary origin, present only in primates, although exogenously applied human B7-1 (hB7-1) binds murine p75 due to the extensive conservation of p75. We mapped the B7-1 surface responsible for p75 engagement and demonstrated that it includes regions known to interact with CTLA-4/CD28 and extends to additional surface regions. Given this overlap, CLTA-4/CD28 directly compete with p75 for binding to hB7-1. Exposure of murine hippocampal neurons in vitro to hB7-1 acutely alters dendritic and spine morphology, with loss of postsynaptic protein PSD95 and microtubule discontinuity in a p75-dependent manner. Abatacept, an FDA-approved therapeutic protein (CTLA-4-Fc), inhibits these effects. In vivo injection of hB7-1 into the murine subiculum, a hippocampal region affected in Alzheimer’s Disease, results in acute p75-dependent pruning of dendritic spines. To study the effects of hB7-1 in the intact animal, and in models of neurodegeneration, we developed a chimeric humanized B7-1 knock-in mouse. Our long-term goal is to develop monoclonal antibodies that specifically block hB7-1:p75 engagement for the prevention of neurodegeneration, and we have identified two such monoclonal antibodies that block hB7-1:p75 synapse elimination at 10nM concentration. Aim 1 will further evaluate and prioritize these and other monoclonal antibodies to develop additional reagents with broad epitope coverage. In Aim 2, our two lead antibodies, and other prioritized antibodies, will be evaluated using hippocampal neuron cultures for effects on blocking synaptic elimination and negative dendritic remodeling. Aim 3 will evaluate the in vivo effectiveness of select antibodies on preventing hB7-1 spine elimination and behavioral impairment by blocking the interaction of immune cell-expressed B7-1 with neuronal p75 in WT, chimeric B7-1 and an AD mouse model. These studies represent conceptual, mechanistic and therapeutic advances by (1) extending our understanding of immune:neuronal interactions that promote neurodegeneration; (2) identifying mechanisms that exist in humans, but not mice, to overcome existing limitations of murine models; (3) identifying preclinical therapeutics for aging populations.

衰老的大脑的特点是促炎和抗炎之间的稳态平衡缓慢恶化