Genes regulating M cell differentiation

调节M细胞分化的基因

• 批准号: 8226561
• 负责人: DAVID D LO
• 金额: $ 38万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8226561
• 关键词: Abbreviations; Affect; Antigens; Autoimmune Diseases; B-Lymphocyte Subsets; B-Lymphocytes; Bacteria; Bronchus-Associated Lymphoid Tissue; Caliber; Cell Count; Cell Differentiation process; Cell Lineage; Cells; Cellular biology; Cholera Toxin; Complex; Data; Dendritic Cells; Deoxyuridine; Development; Enterocytes; Epithelial; Epithelial Cells; Epithelium; Equilibrium; Feedback; Gene Expression Profile; Generations; Genes; Goals; Immune; Immune system; Immunity; Immunologic Surveillance; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Intestinal Mucosa; Intestines; Invaded; Lateral; Ligands; Lymphocyte Subset; Lymphoid Follicle; Lymphoid Tissue; M cell; Maintenance; Mediating; Microbe; Mucosal Immune Responses; Mus; Nose; Play; Process; Production; Regulation; Role; Salmonella infections; Secretory Immunoglobulin A; Shapes; Signal Transduction; Specific qualifier value; Stem cells; Structure of aggregated lymphoid follicle of small intestine; TNF gene; TNFRSF1A gene; Testing; Tissues; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-Beta; Villous; Villus; Virus; Work; commensal microbes; cytokine; immune activation; intestinal epithelium; jagged1 protein; lymphotoxin beta receptor; notch protein; particle; pathogen; progenitor; receptor; stem; transcytosis

DESCRIPTION (provided by applicant): We are studying the development and function of mucosal M cells and their role in immune surveillance. Our goal is to define the genes and mechanisms involved in the development and function of mucosal M cells. By identifying the critical steps and mechanisms in M cell biology, we will begin to establish their specific role in the mucosal immune response and its ability to mediate mucosal tolerance and the balance with commensal microbes. Our Working Hypothesis in these studies is that specific TNF Superfamily and TNF Receptor Superfamily genes along with coordinated expression of Jagged-1 mediate cellular interactions that specify M cell development and function. We will study two main steps in M cell development, defined by our studies on CD137- deficient mice. The first step is the commitment of M cell lineage progenitors from stem cells, which is dependent in part on ligands for the lymphotoxin ¿ receptors and the TNFa receptors. Expression of Jagged-1 by the established M cells may also inhibit generation of M cells from adjacent enterocytes. The second step, functional maturation of M cells, appears to be dependent on interactions between M cells and basolateral pocket B lymphocytes. Here, CD137 (TNFRSF9) and its ligand CD137L, may be an important signaling pair in this interaction. Two specific aims examine these components of our hypothesis: (1) How is M cell lineage commitment and development regulated by Jagged-1/Notch interactions? (2) What are the specific CD137/CD137L cellular interactions regulating M cell basolateral pocket formation and M cell functional development? Regulation of the steady state numbers of M cells in the intestinal mucosa is a dynamic process, and the process depends on an active interplay between crypt stem cells, intestinal epithelium, and lymphocyte subpopulations. This process works in parallel among Peyer's patch, Isolated Lymphoid Follicles, and Villus M cells, and will be shaped by intestinal infection and inflammation (e.g., in Inflammatory Bowel Disease). Thus, a feedback loop exists where M cell transcytosis of lumenal microbes induces mucosal immune activation, which in turn drives production of new M cells. Our studies will provide important details on both the positive and negative regulators of this process. PUBLIC HEALTH RELEVANCE: M cells are a specialized subset of epithelial cells overlying mucosal lymphoid tissues such as intestinal Peyer's patches; they have a unique selective particle transcytosis capability that enables particles as large as a few microns in diameter to cross the epithelial barrier. Thus, M cells play a central role in host-pathogen interactions. Curiously, while the host mucosal immune system relies on this transcytosis function to detect pathogens and induce protective secretory IgA immunity, many pathogenic viruses and bacteria also hijack M cell transcytosis to invade. This paradoxical dual role of M cells in infection and immunity becomes even more complex as infection- and autoimmune disease- induced inflammatory cytokines affect M cell differentiation. Regulation of the steady state numbers of M cells in the intestinal mucosa is a dynamic process, and the process depends on an active interplay between crypt stem cells, intestinal epithelium, and lymphocyte subpopulations. This process works in parallel among Peyer's patch, Isolated Lymphoid Follicles, and Villus M cells, and will be shaped by intestinal infection and inflammation (e.g., in Inflammatory Bowel Disease). Thus, a feedback loop exists where M cell transcytosis of lumenal microbes induces mucosal immune activation, which in turn drives production of new M cells. Our studies have identified a set of genes that appear to regulate M cell lineage commitment (Jagged-1, Notch) and functional development (CD137, CD137L) and interactions between M cells and associated B lymphocytes. The proposed project will provide important details on the role of these genes in both the positive and negative regulation of M cell development.

描述（由申请人提供）：我们正在研究粘膜M细胞的发育和功能及其在免疫监视中的作用。我们的目标是确定参与粘膜M细胞的发育和功能的基因和机制。通过确定M细胞生物学中的关键步骤和机制，我们将开始建立它们在粘膜免疫应答中的特定作用及其介导粘膜耐受和与肠道微生物平衡的能力。我们在这些研究中的工作假设是，特定的TNF超家族和TNF受体超家族基因沿着Jagged-1的协调表达介导了指定M细胞发育和功能的细胞相互作用。我们将研究M细胞发育的两个主要步骤，这是我们在CD 137缺陷小鼠上的研究所定义的。第一步是来自干细胞的M细胞谱系祖细胞的定型，其部分依赖于光敏素受体和TNF α受体的配体。由已建立的M细胞表达Jagged-1也可抑制来自相邻肠上皮细胞的M细胞的产生。第二步，M细胞的功能成熟，似乎是依赖于M细胞和基底外侧袋B淋巴细胞之间的相互作用。在此，CD 137（TNFRSF 9）及其配体CD 137 L可能是这种相互作用中重要的信号对。两个具体的目标检查我们的假设的这些组成部分：（1）如何是M细胞谱系的承诺和发展的Jagged-1/Notch相互作用的调节？(2)CD 137/CD 137 L细胞相互作用调节M细胞基底外侧袋形成和M细胞功能发育的特异性是什么？ 肠粘膜中M细胞稳态数量的调节是一个动态过程，该过程依赖于隐窝干细胞、肠上皮和淋巴细胞亚群之间的积极相互作用。这一过程在派伊尔集合淋巴结、分离的类淋巴滤泡和绒毛M细胞之间平行进行，并将通过肠道感染和炎症（例如，炎症性肠病）。因此，存在反馈回路，其中内腔微生物的M细胞转胞吞作用诱导粘膜免疫活化，这反过来驱动新M细胞的产生。我们的研究将提供关于这一过程的积极和消极调节剂的重要细节。 公共卫生关系：M细胞是覆盖粘膜淋巴组织（如肠派尔集合淋巴结）的上皮细胞的特化子集;它们具有独特的选择性颗粒转胞吞能力，使直径为几微米的颗粒能够穿过上皮屏障。因此，M细胞在宿主-病原体相互作用中发挥核心作用。奇怪的是，虽然宿主粘膜免疫系统依赖于这种转胞吞功能来检测病原体并诱导保护性分泌型伊加免疫，但许多病原性病毒和细菌也劫持M细胞转胞吞来入侵。M细胞在感染和免疫中的这种矛盾的双重作用变得更加复杂，因为感染和自身免疫性疾病诱导的炎性细胞因子影响M细胞分化。 肠粘膜中M细胞稳态数量的调节是一个动态过程，该过程依赖于隐窝干细胞、肠上皮和淋巴细胞亚群之间的积极相互作用。这一过程在派伊尔集合淋巴结、分离的类淋巴滤泡和绒毛M细胞之间平行进行，并将通过肠道感染和炎症（例如，炎症性肠病）。因此，存在反馈回路，其中内腔微生物的M细胞转胞吞作用诱导粘膜免疫活化，这反过来驱动新M细胞的产生。我们的研究已经确定了一组似乎调节M细胞谱系定型（Jagged-1，Notch）和功能发育（CD 137，CD 137 L）以及M细胞和相关B淋巴细胞之间相互作用的基因。拟议的项目将提供这些基因在M细胞发育的正向和负向调节中的作用的重要细节。