2011-08-012024-05-17https://scholars.lib.ntu.edu.tw/handle/123456789/691239摘要：結核分枝桿菌是一種會導致人類結核病的病原體, 全球每年大約有兩百萬人會死於結核病。由小鼠模式, 我們定位了一個染色體上能控制宿主對結核分枝桿菌感染產生感受性的基因座, sst1, 並進一步找出位在此sst1 區域內的候選基因, Ipr1。表現 Ipr1 能抑制結核分枝桿菌在巨噬細胞內的增殖, 並將被感染的巨噬細胞從可能形成細胞壞死轉變為細胞凋萎。 SP110 是人類 IPR1 蛋白的相對應蛋白質, 這兩個蛋白質會在細胞核內呈現斑點的結構而且是核體的組成分。這類核蛋白的功能可能是作為轉錄共調控因子來調控轉錄作用、核染質改組、及去氧核醣核酸的複製。此外, 和 SP110 相似的SP100 蛋白則具有腫瘤抑制的特性。我們先前的研究顯示 SP110 基因有許多同位體,而這些同位體的產生可能是由於選擇性剪接所造成的, 且發炎反應能調控 SP110 基因的選擇性剪接。我們假設不同的 SP110 蛋白質同位體會被不同的表現、有不同的細胞位置、且各別和不同的分子作用來執行多樣性但不重複的細胞功能, 例如調控轉錄作用、抑制腫瘤細胞生長、促進細胞凋萎、以及調節宿主對病原體感染的免疫反應。本計劃將探索 SP110 蛋白質的不同功能並找出它們的分子作用機制。以這些發現作基礎,我們將可能把重要的生物訊息轉譯成有效的疾病治療策略。<br> Abstract: Mycobacterium tuberculosis (Mtb) is an intracellular pathogen responsible for humantuberculosis (TB) and causes approximately two million people deaths annually in the world.In mouse models, we have mapped a chromosomal region, sst1 locus (supersusceptibility totuberculosis 1), which controls host susceptibility to Mtb infection, and further identified thecandidate gene, Ipr1 (intracellular pathogen resistance 1), within the region. Expression of theIpr1 gene limits multiplications of Mtb in macrophages in vitro as well as alters cell deathmodes of Mtb infected-macrophages from necrosis to apoptosis, suggesting that IPR1 proteinmay play a key role in apoptosis signaling. SP110 protein is the closest human homologue ofmouse IPR1 protein, and both proteins have been shown to form speckled structures innucleus and are components of nuclear bodies (NBs). This type of nuclear proteins mayfunction as a transcriptional co-regulator regulating transcription, chromatin re-modeling andDNA replication. Besides, it has been shown that components of nuclear bodies includingSP100, which belongs to the same Sp100/Sp140 family of nuclear body components as SP110,may function as a potent tumor suppressor. Our previous studies also indicate that the SP110gene has several isoforms, which may result from alternative splicing of SP110 mRNA, andthe inflammation could regulate the alternative splicing of SP110 gene. We hypothesize thatdifferent SP110 isoforms are differentially expressed in response to different stimuli, havedifferent subcellular localizations, and bind their own subset of interaction partners to fulfilldiverse but non-redundant functions in the cells, such as regulating transcription, controllingtumor cell growth, promoting apoptosis and mediating cellular responses to pathogeninfections.In this project, we propose to explore a variety of functions of SP110 protein and furtheridentify the molecular mechanisms mediated by the SP110 gene in the cells. The specific aimsare the following:Specific Aim 1: To identify proteins that interact with different SP110 isoforms in the nucleiof interferon-activated and Mtb-infected macrophages.Specific Aim 2: To identify DNAs targeted by the SP110-containing nuclear proteincomplexes.Specific Aim 3: To investigate the underlying molecular mechanisms mediated by SP110 toregulate modes of cell death.Specific Aim 4: To determine the possible effects of SP110 protein on tumor suppression.On the basis of these findings in the project, it would be possible to translate significantbiological information into effective treatment strategies for tumors and infectious diseases.scapula dyskinesisconscious controlEMG biofeedbackintensive scapula-focused training