Interrogating unique DC adaptations to tissue to promote barrier immunity and tolerance

探究 DC 对组织的独特适应，以促进屏障免疫和耐受性

基本信息

批准号：
10378337
负责人：
Niroshana Anandasabapathy
金额：
$ 74.12万
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：
2022
资助国家：
美国
起止时间：
2022-03-01 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10378337
关键词：
2019-nCoV ATAC-seq Adoptive Cell Transfers Antigens Apoptotic Autoantigens Autoimmunity Basic Science Behavior Biology Blood Bone Marrow CISH gene Candida Cell Maturation Cells Cellular biology Chromatin Clinical Cues Data Dendritic Cells Development Disease Environment Equilibrium Face Foundations Genes Goals Health Homeostasis Human IFNG gene Immune Immune Tolerance Immune system Immunity Individual Infection Inflammation Inflammatory Influenza Interferon Type II Intervention Knowledge Licensing LoxP-flanked allele Lung Maps Measures Modeling Molecular Molecular Target Mus Myelogenous Organism Pathogen detection Pathogenesis Pathogenicity Pathway interactions Pattern Peptide/MHC Complex Peripheral Pharmacology Population Positioning Attribute Proteins Psoriasis Public Health Publishing Reporter Self Tolerance Signal Transduction Simplexvirus Site Skin Source Stimulus Surveys Systems Biology T-Lymphocyte Testing Time Tissue Differentiation Tissues Transcript Tumor Immunity Vaccination Vaccines Viral Cancer Virus Vitiligo Work autoinflammation cancer cell cell motility cell type clinically relevant combat conditioning drug development immunogenic improved in vivo insight lymphoid organ melanoma modifiable behavior neuroinflammation pathogen preservation prevent progenitor programs response tissue repair transcription factor transcriptome tumor vaccination strategy viral DNA

项目摘要

Project summary: The immune system faces the external world and encounters pathogens, including viruses in barrier tissues (e.g. skin, lung, and gut). There the immune system must detect and respond to pathogens, while simultaneously preventing autoimmunity and promoting tissue repair. Dendritic cells (DC) in tissue are the key cells which balance self-tolerance (preventing destruction of our bodies tissues) with pathogen surveillance. The goal of this application is to understand how DCs develop uniquely and are adapted in the tissue to perform and balance these functions. We have recently identified an important new mechanism, and a new molecular target that dictates how DC in tissues differentiate in ways that impact their function. The goal of this proposal is to gain a deeper understanding of DC biology along this regulatory axis, as a critical first step to intervene upon tissue DC to restore health, when dysregulated. This would advance better immunization strategies as tissue DCs are necessary for vaccine, viral, and cancer immunity. This application enables us to now test, for the first time, how our myeloid compartment is architected to balance immune tolerance and pathogen surveillance in barrier tissue sites. Upon completion of this project we will understand how DCs in tissue are locally conditioned to behave in a site- specific manner. We will gain an appreciation of how shared environmental sensing patterns are balanced against individual cell identities, and tailored to specific pathogenic contexts. We will understand how local cues modify the behavior of DCs, positioning us to test this in disease states. We will also identify DC behaviors that are modifiable by local cues, enabling improved intervention on DC during disease pathogenesis and a better model for successful DC development to improve adoptive cell therapy. The insights here are foundational, fill a critical knowledge gap, and represent basic science advances needed to advance human health.

项目概要：免疫系统面对外部世界并遇到病原体，包括屏障组织中的病毒（例如，病毒）。皮肤、肺和肠道）。免疫系统必须检测病原体并对其做出反应，同时预防自身免疫并促进组织修复。组织中的树突状细胞（DC）是发挥作用的关键细胞。平衡自我耐受性（防止我们身体组织的破坏）与病原体监测。该应用的目标是了解 DC 如何独特地发育并在组织中适应以执行并平衡这些功能。我们最近发现了一个重要的新机制和一个新的分子决定组织中 DC 如何以影响其功能的方式分化的目标。该提案的目标是沿着这个调控轴更深入地了解 DC 生物学，作为干预的关键第一步当失调时，组织 DC 可以恢复健康。这将推进更好的免疫策略作为组织 DC 是疫苗、病毒和癌症免疫所必需的。该应用程序使我们现在能够进行第一次测试时间，我们的骨髓室是如何构建的，以平衡免疫耐受和病原体监测屏障组织部位。完成这个项目后，我们将了解组织中的树突状细胞如何局部调节以在某个位点表现—— 具体方式。我们将了解如何平衡共享的环境感知模式针对个体细胞身份，并针对特定的致病环境进行定制。我们将了解当地线索如何改变 DC 的行为，使我们能够在疾病状态下对其进行测试。我们还将识别 DC 行为可以通过局部线索进行修改，从而能够在疾病发病机制期间改进对 DC 的干预，并更好地成功开发 DC 以改善过继细胞疗法的模型。这里的见解是基础性的，填补关键的知识差距，代表了促进人类健康所需的基础科学进步。