2021-01-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/654594小兒生長遲緩異常(FTT, children failure to thrive)為一成長的體重始終低於同年齡與性別的第三至第五百分位以下的疾病。對於家庭與社會成本的付出非常嚴重。造成的原因非常多樣，包括:遺傳、基因調控、環境飲食營養等因素，最後導致體內賀爾蒙系統失調，各組織器官無法正常受到刺激生長。微核醣核酸近年來被發現可以經由許多方式，包括:透過母體胎盤傳送或是直接影響個體內分泌系統等，調控特定基因表現影響生長發育，不過目前尚無明確機制或是動物模型被建立。本研究以在微核醣核酸137缺損的小鼠上發現有嚴重的生長遲緩、出生後短期死亡、且肝臟產生與血中循環的胰島素生長因子1(IGF-1)有顯著缺乏做為基礎，預計進行三年期的深入研究。長遠的目標在於了解為核醣核酸透過調控內分泌系統影響生長遲緩的機制，做為臨床診斷或是治療的標的；因此，本計畫的中心假說為:微核醣核酸137可以透過調控生長激素/胰島素生長因子1的訊息傳遞軸，影響全身各器官受賀爾蒙刺激而生長。為了完成本研究，將有三個主要的特異性目標預計被執行與達成，包括:1.全面深入了解微核醣核酸137缺損小鼠模型的生長遲緩表現型；2.深究微核醣核酸137缺損的全身賀爾蒙系統與對應器官反應；3.鑑定微核醣核酸137對於生長遲緩異常現象的主要標的調控基因，了解其分子機制。本計畫將是第一個以核醣核酸缺損建立的生長遲緩異常動物模型，除了可以剖析機制外，亦可做為相關疾病的研究工具，長期則可提供臨床病患在診斷與治療上的應用。 Children failure to thrive (FTT) is a disease with the weight consistently below the 3rd to 5th percentile for age and sex. It has a great impact to the cost of family and society. The cause is multiple factors including genetic hereditary, gene regulation, environment, and nutrition followed by dysregulation of endogenous hormone system and failure to thrive of each organ. MicroRNA recently had been reported to regulate body growth and development by targeting specific genes via various strategies such as maternal transferring or endocrine system modulation. However, the fundamental mechanism remains to be clarified and the ideal animal model is required. This three-year proposal is based on the dramatic phenomenon identified on miR-137 deficient (miR-137-/-) mice. It exhibited a severe growth retardation, postnatal early death, and extreme reduced Insulin Growth Factor-1 (IGF-1) level in liver and circulating blood. The long term goal is to elucidate the mechanism of microRNA in regulating body growth and development via modulating endocrine system. Therefore, the central hypothesis is miR-137 can affect hormone stimulated organ growth by regulating growth hormone/IGF-1 (GH/IGF-1) axis. To proof this hypothesis, three specific aims will be achieved including: 1. To comprehensively and in-depth understanding of the growth retardation phenomenon in miR-137-/- mice; 2. To investigate the GH/IGF-1 hormonal system of miR-137-/- mice and the responsiveness in each organ; 3. To identify the major target gene of miR-137 for growth retardation and to understand its underlying molecular mechanism. This proposal is the first time to establish an animal model for FTT based on microRNA deficiency. With the achievement of this proposal, it can not only clarify the molecular mechanism but also be a tool for studying in related diseases. For a long term goal, it can provide a diagnostic marker or a therapeutic target in clinical application.微核醣核酸137生長遲緩基因缺損動物模型生長激素/胰島素生長因子1內分泌系統miR-137growth retardationgene deficient animal modelGH/IGF-1endocrine system