Elucidating the Fundamental Biology of Memory Regulatory T cells in Skin

阐明皮肤记忆调节 T 细胞的基本生物学

基本信息

批准号：
8898017
负责人：
Michael David Rosenblum
金额：
$ 17.38万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898017
关键词：
Activities of Daily Living Address Adverse effects Antigens Applications Grants Attenuated Autoimmune Process Autoimmune Responses Autoimmunity Biological Models Biology Cell physiology Cells Chronic Clinical Cutaneous Data Disease EGFR inhibition Epidermal Growth Factor Receptor Epithelial Future Gene Expression Profile Generations Goals Hair follicle structure Health Homeostasis Human Immune Immune Tolerance Immune system Inflammation Inflammatory Knowledge Lesion Maintenance Malignant - descriptor Malignant Neoplasms Mediating Memory Molecular Mus Nature Pathway interactions Patients Phenotype Play Population Process Psoriasis RNA Sequences Regulation Regulatory T-Lymphocyte Research Role Skin Skin Cancer Skin Neoplasms Suppressor-Effector T-Lymphocytes T-Lymphocyte Testing Time Tissues Transgenic Mice Translating Translations Tumor Tissue Wound Healing cytokine high reward high risk human disease immune function in vivo innovation insight keratinocyte mouse model novel novel strategies pre-clinical prevent repaired research study skin disorder stem transcriptome sequencing treatment strategy tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): Regulatory T cells (Tregs) play a major role in establishing and maintaining immune tolerance in tissues, with a predilection for epithelial barriers such as skin. Augmenting the function of these cells has significant potential to treat cutaneous inflammation and inhibiting the function of these cells may prove efficacious in treating cutaneous malignancies. We recently characterized a unique population of Tregs in both murine and human skin, termed memory Tregs (mTreg). These cells are highly activated suppressors that are stably maintained in skin for relatively long periods of time and have enhanced functional capacity to attenuate inflammation. The underlying theme of this proposal is to functionally dissect the dominant pathways utilized by mTregs in skin and develop novel strategies to specifically augment or inhibit the function of these cells in a tissue-specific fashion. To achieve this goal, we will utilize novel technological advances in our ability to disset the function of immune cells in human skin in vivo. This is a high-risk high-reward proposal with the potential for direct translation to human disease. Its innovativeness stems from the fact that we will utilize newly established transgenic mouse model systems to inform experiments in humanized mice, enabling us to effectively and efficiently translate findings from mice to humans. On a basic level, we will gain critical mechanistic insight as to how mTregs function in skin and, on a translational level, we will exploit this knowledge to develop new treatment strategies for inflammatory or malignant skin disease.

描述（由申请人提供）：调节性 T 细胞 (Treg) 在组织中建立和维持免疫耐受方面发挥着重要作用，尤其偏爱皮肤等上皮屏障。增强这些细胞的功能具有治疗皮肤炎症的巨大潜力，而抑制这些细胞的功能可能可以有效治疗皮肤恶性肿瘤。我们最近在小鼠和人类皮肤中描述了一个独特的 Tregs 群体，称为记忆 Tregs (mTreg)。这些细胞是高度活化的抑制因子，可以在皮肤中稳定维持相对较长的时间，并具有增强的减轻炎症的功能能力。该提案的基本主题是从功能上剖析皮肤中 mTreg 所利用的主要途径，并开发新策略以组织特异性方式特异性增强或抑制这些细胞的功能。为了实现这一目标，我们将利用新技术进步来破坏人体皮肤体内免疫细胞的功能。这是一个高风险高回报的提议，有可能直接转化为人类疾病。其创新性源于这样一个事实：我们将利用新建立的转基因小鼠模型系统为人源化小鼠实验提供信息，使我们能够有效且高效地将小鼠的发现转化为人类。在基础层面上，我们将获得关于 mTregs 如何在皮肤中发挥作用的关键机制见解，在转化层面上，我们将利用这些知识来开发针对炎症或恶性皮肤病的新治疗策略。