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：
10579963
负责人：
Niroshana Anandasabapathy
金额：
$ 73.2万
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/10579963
关键词：
2019-nCoV ATAC-seq Adoptive Cell Transfers Antigen Presentation 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 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 NF-kappa B Organism Pathogen detection Pathogenesis Pathogenicity Pathway interactions Pattern Peptide/MHC Complex Peripheral Population Positioning Attribute Proteins Psoriasis Public Health Publishing Reporter Self Tolerance Signal Transduction Simplexvirus Site Skin Stimulus Surveys Systems Biology T-Lymphocyte Testing Time Tissue Differentiation Tissues Transcript Tumor Immunity Vaccination Vaccines Viral 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 pharmacologic preservation prevent progenitor programs response source localization 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.

项目摘要：免疫系统面临外部世界并遇到病原体，包括屏障组织中的病毒（例如，皮肤，肺和肠）。那里的免疫系统必须检测并应对病原体，同时防止自身免疫和促进组织修复。组织中的树突状细胞（DC）是关键细胞平衡自我耐受性（防止破坏我们的身体组织）和病原体监测。该应用的目的是了解DC如何独特地发展并在组织中进行调整以执行并平衡这些功能。我们最近确定了一种重要的新机制和一个新的分子决定组织中直流以影响其功能的方式进行区分的目标。该提议的目的是为了深入了解沿该调节轴的直流生物学，作为干预的关键第一步在失调时，组织DC可以恢复健康。作为组织，这将提高更好的免疫策略 DC对于疫苗，病毒和癌症免疫是必需的。此应用程序使我们现在可以测试第一个时间，我们的髓样室的构建方式如何平衡免疫耐受性和病原体监测屏障组织部位。完成该项目后具体方式。我们将对共享环境感应模式如何平衡表示赞赏针对单个细胞的身份，并针对特定的致病背景量身定制。我们将了解本地提示修改DC的行为，定位我们在疾病状态下进行测试。我们还将确定DC行为可以通过局部线索进行修改，从而在疾病发病机理期间改善了对DC的干预，并且更好成功开发的模型以改善收养细胞疗法。这里的见解是基本的，填充批判知识差距，代表进步人类健康所需的基础科学进步。