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.

项目概要/摘要保护性清除描述了去除膜完整的细胞或细胞部分的过程不诱导促炎症反应；它是正常发展的核心模式跨组织和门的稳态。在受调节和抗炎的情况下执行此过程时尚需要一系列活动的精心编排，包括受体介导的活动吞噬作用、溶酶体形成和细胞内降解。保护间隙起着特别重要的作用在维持中枢神经系统（CNS）功能和稳态方面发挥着重要作用。这溶酶体贮积症是一个广泛的疾病家族，其特征是保护性失调中枢神经系统的清除。 Batten 病是一类 13 种致命性神经退行性溶酶体储存病通常出现在儿童期的疾病，包括最常见的遗传性儿科疾病全世界的神经退行性疾病。巴顿病的病理学与突触功能障碍有关和中枢神经系统中的自身抗体沉积。该疾病的所有基因图谱形式都是单基因的，由 13 种蜡质脂褐质沉积症 (cln) 基因之一的突变引起。尽管成功绘制了 cln 基因，在空间和时间上控制 CLN 蛋白的细胞生物学机制仍然是一个开放的问题问题。进一步了解 CLN 蛋白功能的基本机制可能会确定治疗巴顿病的新途径。该提案的目标是阐明分子和内源性吞噬细胞保护性清除的细胞机制并设计通过编程吞噬细胞消除自身抗原抗体复合物来进行治疗中枢神经系统具有抗炎作用。该项目将使用三个强大的模型系统，包括活的吞噬细胞和明确的目标来定义潜在的分子和细胞机制保护间隙。在目标 1 中，我们将使用保护间隙的简化细胞模型来探索我们最近发现了 CLN 蛋白和保守的吞噬细胞受体之间的联系。在目标 2 中，我们将使用视网膜内源性保护间隙的新模型来系统地定义每个 CLN 蛋白在保护性清除过程中的功能。在目标 3 中，我们将利用我们在免疫方面的专业知识细胞编程改造吞噬细胞，通过消除中枢神经系统中的抗原抗体复合物保护性清除并在先进的小鼠中枢神经系统巨噬细胞移植中体内测试这些分子模型。完成这些目标将阐明保护性清除的分子机制，定义巴顿病突变如何失调该过程，并研究其治疗潜力合成受体以消除中枢神经系统中的抗原抗体复合物，从而发挥抗炎作用方式。