Elucidating the Functional Role of Layilin Expression on Regulatory T cells in Skin

阐明 Layilin 表达对皮肤调节性 T 细胞的功能作用

• 批准号: 9372498
• 负责人: Michael David Rosenblum
• 金额: $ 20.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-04 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9372498
• 关键词: Actins; Address; Adhesions; Antigens; Applications Grants; Autoimmune Diseases; Autoimmunity; Behavior; Biological Assay; Biology; C Type Lectin Receptors; CRISPR/Cas technology; Cell Adhesion; Cell Mobility; Cell physiology; Cells; Clinical; Coculture Techniques; Confocal Microscopy; Cutaneous; Cytoskeleton; Data; Disease; Extracellular Domain; Extracellular Matrix; Fibroblasts; Goals; Homeostasis; Human; Image; Immune; Immune Tolerance; Immune system; Impaired wound healing; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interferon Type II; Knowledge; Literature; Measures; Mediating; Methodology; Microscopy; Molecular; Monoclonal Antibodies; Morphology; Mus; Pathway interactions; Patients; Phase; Play; Population; Production; Proteins; Regulatory T-Lymphocyte; Reporting; Role; Signal Transduction; Skin; Skin Cancer; Skin wound; System; Testing; Th1 Cells; Therapeutic; Tissues; Translating; Wound Healing; cell behavior; cell motility; experimental study; genome editing; innovation; interstitial; macrophage; migration; novel; overexpression; peripheral blood; protein function; stem; tool; transcriptome; transcriptome sequencing; two-photon; wound closure

Project Summary/Abstract Regulatory T cells (Tregs) play a major role in establishing and maintaining immune homeostasis. The function of these cells depends on the tissues in which they reside. We have previously shown that both murine and human skin contain a unique population of Tregs; however, the mechanisms utilized by these cells to mediate their functions in this tissue are largely unknown. Using an biased discovery approach, we identified LAYN (layilin), a novel C-type lectin receptor-like molecule, to be preferentially and highly expressed on Tregs in skin in an evolutionarily conserved manner. Layilin has been shown to interact with the extracellular matrix through its extracellular domain and with the actin cytoskeleton through its intracellular domain, suggesting that this molecule facilitates cell mobility and migration within tissues. Expression of layilin on immune cells has not been reported and the function of this protein in the context of tissue inflammation is entirely unknown. The overall goal of this proposal is to elucidate the functional role of layilin expression on Tregs in murine and human skin. We hypothesize that Tregs utilize layilin to localize and/or migrate within skin in the steady-state and/or during inflammation. In doing so, we speculate that this molecule plays a major role in Treg function in this tissue. To test this hypothesis, we have generated mice that are deficient in layilin, as well as systems to overexpress and genetically delete layilin in human Tregs. The experiments outlined herein represent a conceptually and technically innovative, systematic approach to better understand how Tregs utilize a novel molecule to regulate inflammation in skin. Our results may have implications for clinical approaches focused on functionally manipulating tissue-specific Tregs.

项目概要/摘要 调节性 T 细胞 (Treg) 在建立和维持免疫稳态方面发挥着重要作用。这些的作用 细胞取决于它们所在的组织。我们之前已经证明，小鼠和人类的皮肤都含有 独特的 Tregs 群体；然而，这些细胞在该组织中介导其功能的机制是 很大程度上不为人知。使用有偏见的发现方法，我们发现了 LAYN (layilin)，一种新型 C 型凝集素受体样 分子，以进化保守的方式在皮肤中的 Tregs 上优先且高度表达。拉伊林有 已被证明通过其细胞外结构域与细胞外基质以及肌动蛋白细胞骨架相互作用 通过其细胞内结构域，表明该分子促进细胞在组织内的移动和迁移。 尚未报道 Layilin 在免疫细胞上的表达以及该蛋白在组织中的功能 炎症是完全未知的。该提案的总体目标是阐明layilin表达的功能作用 对小鼠和人类皮肤中的 Tregs 的影响。我们假设Tregs利用layilin在皮肤内定位和/或迁移 在稳态和/或炎症期间。在此过程中，我们推测该分子在 Treg 在该组织中发挥作用。为了验证这一假设，我们培育了缺乏莱伊林以及莱伊林的小鼠。 系统在人类Tregs中过度表达并基因删除layilin。本文概述的实验代表 概念和技术上创新的系统方法，以更好地理解 Tregs 如何利用新型分子 调节皮肤炎症。我们的结果可能会对注重功能的临床方法产生影响 操纵组织特异性 Tregs。