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Elucidating and harnessing the molecular mechanisms of protective clearance in endogenous and engineered phagocytes

阐明和利用内源性和工程化吞噬细胞保护性清除的分子机制

基本信息

批准号：
10729935
负责人：
Adam Patrick Williamson
金额：
$ 41.86万
依托单位：
BRYN MAWR COLLEGE
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：
2023-09-08 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10729935
关键词：
Anti-Inflammatory Agents Antibodies Antigen-Antibody Complex Antigens Apoptotic Autoantibodies Autophagocytosis Behavior Binding Biological Biological Assay Biological Models Birth Brain CRISPR/Cas technology Cell Culture Techniques Cell model Cell physiology Cells Central Nervous System Central Nervous System Diseases Childhood Chloride Channels Chlorides Chronic Collaborations Collection Data Deposition Development Disease Drosophila genus Elements Engineering Excision Extracellular Domain Family Functional disorder Genes Genetic Goals Homeostasis Human IgG Receptors Immune In Vitro Inflammation Inflammatory Inflammatory Response Ingestion Inherited Knowledge Learning Ligands Link Lysosomes Macrophage Maps Measures Mediating Membrane Mendelian disorder Methods Modeling Molecular Mus Mutate Mutation Nerve Degeneration Neurodegenerative Disorders Neuronal Ceroid-Lipofuscinosis Orthologous Gene Pathology Phagocytes Phagocytosis Play Process Protein Dynamics Proteins Recovery Retina Retinal Degeneration Rod Outer Segments Role Signal Transduction Spielmeyer-Vogt Disease Structure of retinal pigment epithelium Synapses System Testing Texas Therapeutic Time Tissues Transplantation Tumor Antigens Work axon injury cancer cell design extracellular in vivo mutant novel particle programs protein function receptor reconstitution retinal rods success transplant model

项目摘要

Project Summary/Abstract Protective clearance describes the process of the removal of membrane-intact cells or parts of cells without induction of pro-inflammatory responses; it is a central mode of normal development and homeostasis across tissues and phyla. Executing this process in a regulated and anti-inflammatory fashion requires exquisite orchestration of a collection of activities including receptor-mediated phagocytosis, lysosome formation, and intracellular degradation. Protective clearance plays a particularly important role in maintaining function and homeostasis in the central nervous system (CNS). The lysosomal storage disorders are a broad family of diseases characterized by dysregulated protective clearance in the CNS. Batten disease is a class of 13 fatal neurodegenerative lysosomal storage disorders that usually appear in childhood and comprise the most common inherited pediatric neurodegenerative disease worldwide. The pathology of Batten disease is linked to synaptic dysfunction and auto antibody deposition in the CNS. All genetically mapped forms of the disease are monogenic, caused by mutations in one of 13 ceroid lipofuscinosis (cln) genes. Despite the success mapping the cln genes, the cell biological mechanisms governing the CLN proteins in space and time remain an open problem. Further understanding of the fundamental mechanisms underlying CLN protein function may identify new avenues to treat Batten disease. The goal of this proposal is to elucidate the molecular and cellular mechanisms underlying protective clearance in endogenous phagocytes and engineer the process in for therapy by programming phagocytes to eliminate auto antigen-antibody complexes in the CNS in an anti-inflammatory manner. This project will use three powerful model systems comprised of living phagocytes and defined targets to define the molecular and cellular mechanisms underlying protective clearance. In Aim 1, we will use a simplified cell model of protective clearance to explore a connection we recently discovered between a CLN protein and a conserved phagocyte receptor. In Aim 2, we will use a novel model of endogenous protective clearance in the retina to systematically define the functions of each CLN protein during protective clearance. In Aim 3, we will use our expertise in immune cell programming to engineer phagocytes that eliminate antigen-antibody complexes from the CNS via protective clearance and test these molecules in vivo in an advanced mouse CNS macrophage transplant model. Completion of these aims will clarify molecular mechanisms underlying protective clearance, define how Batten disease mutations dysregulate the process, and investigate the therapeutic potential of synthetic receptors to eliminate antigen-antibody complexes from the CNS in an anti-inflammatory manner.

项目总结/文摘