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https://nccur.lib.nccu.edu.tw/handle/140.119/157166
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| Title: | 淋巴細胞功能缺失在Hoxb8基因剔除鼠之自體免疫與類強迫症行為異常表型中扮演角色之研究
Study of the Roles of Lymphocyte Defects in Autoimmune and Ocd-Like Behavioral Phenotype in Hoxb8 Mutant Mice |
| Authors: | 陳紹寬 |
| Contributors: | 神科所 |
| Keywords: | 強迫症;自體免疫;T細胞
Hoxb8;autoimmune;obsessive compulsive disorder;T cell |
| Date: | 2019-01 |
| Issue Date: | 2025-05-29 11:56:59 (UTC+8) |
| Abstract: | Hoxb8 基因剔除小鼠中的過度理毛行為與強迫症患者的重複行為非常相似，因此被認為是一個可供強迫症研究的模式動物。我們之前的研究顯示Hoxb8 基非字體機制仍不清楚。為研究其血液功能缺陷，我們對的Hoxb8 基因剔除的免疫系統進行進步的分析，結果顯示此突變鼠中有自體免疫症狀的產生，包括自體抗體的產生與B 細胞及T 細胞的異常活化。由於目前尚未有Hox 基因與自體免疫有關的研究報告，另外在包括強迫症在內的許多神經疾病患者體內也發現有自體免疫的現象。在本研究中我們將研究這種自體免疫表型的細胞和分子基礎，以及此表型是否為造成類強迫症行為的原因。我們的初步研究結果指向此自體免疫現象是由CD4+ T 功能異常所造成。我們將分析突變鼠的CD4+ T 細胞刺激後分化與功能是否正常，並對兩種可能與此表型有關的CD4+ T 細胞亞型的功能進行分析。同時我們還會將Hoxb8 基因在T 細胞中條件性敲除以驗證是否功能異常造成此突變鼠之自體免疫表型。另外，我們還將研究此突變鼠中自體免疫現象或其淋巴細胞的缺陷在其異常行為中扮演的角色。我們將研究在Hoxb8 基因剔除鼠中是否產生可攻擊腦部組織的自體抗體，及腦組織中是否有因免疫系統的攻擊造成腦部損傷。同時我們將以遺傳技術使Hoxb8 基因剔除鼠不帶有B細胞，使其無法產生自體抗體，以研究自體免疫與類強迫症行為表型的關係。最後我們將研究T 細胞在非自體免疫的條件下對腦部功能及行為的影響。我們將培養出缺乏T 細胞的野生型及Hoxb8 基因剔除鼠及條件敲除小鼠以進行此項研究。我們的還將分析上述突變鼠腦中各種細胞素的濃度變化，及T 細胞與微膠質細胞或神經細胞間的交互作用。上述研究可能產生在自體免疫的致病機制研究上的重大發現，同時在免疫系統，尤其是T 細胞如何影響行為表現及神經系統功能上，開創一個新個研究空間。
The compulsive grooming behavior observed on Hoxb8 mutant mice has been considered as a mouse analogue of OCD signature symptom repetitive behavior. This behavioral phenotype is caused by hematopoietic defects. However, the mechanisms underlying this phenomenon remain unclear. Our preliminary data revealed that autoimmunity are developed in Hoxb8 mutants. B and T cells are aberrantly activated and plasma level of immunoglobins are elevated. The developmental defects of T cell lineage might lead to the aberrant T cell activation, which could be the cause of this autoimmue phenotype. In this proposal, we will determine the cellular and molecular basis underlying this autoimmune phenotype, as well as examine how the defective T cell functions contribute to the behavioral phenotypes in Hoxb8 mutants. First we will investigate the cellular basis of the autoimmune phenotype. Here we will further examine the CD4+ T cells activations and functions upon stimulation. We will also determine the functions of different CD4+ T cell subtypes, especially those are associated with the pathogenesis of autoimmune diseases, such as regulatory T cell and follicular helper T cells. In addition, the roles of T cell defects and autoimmunity in the development and propagation of excessive grooming phenotype will be studied in this project. Whether brain-specific autoantibodies and tissue damages are developed in Hoxb8 mutant will be determined. Tissue specific conditional mutagenesis strategy will be applied to test how the compulsive grooming phenotype will be developed in lymphocyte or T cell specific Hoxb8 knockout mice. In parallel, T cell- or B cell- deficient mutants on wild type or Hoxb8 knockout background will be generated by genetic ablation to elucidate the roles of T cell in normal brain functions and compulsive behavior development, and the roles of autoreactive B cell and autoantibodies. Finally, the interactions between T cells and neurons or glia will be determined, and cytokine profiles in cerebrum of wild type and mutant brains will be identified. Combing the results, we might discover a new pathway of autoimmune pathogenesis. Moreover, we might provide groundbreaking information of the biological functions of lymphocytes, especially T cells, in CNS physiology. |
| Relation: | 科技部, MOST106-2320-B004-001, 106.08-107.07 |
| Data Type: | report |
| Appears in Collections: | [神經科學研究所] 國科會研究計畫
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