2012-08-012024-05-13https://scholars.lib.ntu.edu.tw/handle/123456789/648335摘要：類固醇荷爾蒙主要由腎上腺、性腺與胎盤所產生。此外，神經系統亦能自行合成具神經活性之類固醇，稱為神經性類固醇。CYP11A1基因產物為膽固醇側鏈截切酶 (cholesterol side-chain cleavage enzyme，P450scc)，催化類固醇荷爾蒙生合成的第一步驟。參與類固醇生成途徑的各種酵素，包括CYP11A1，陸續被發現存在於神經系統，但與腎上腺、性腺相比較，這些類固醇生成基因在腦的表現量非常低，因此對其在腦區的表現分布、轉錄調控機制以及生理功能的研究都非常有限。神經性類固醇可以經由與典型的核內類固醇荷爾蒙受體結合，影響目標基因的表現。但一般認為，神經性類固醇主要會作用於神經傳導物質受體而產生效應，例如調控GABAA 與 NMDA等受體。已知神經性類固醇會影響神經細胞存活、神經新生、軸突生長、髓鞘質形成等作用。動物與人體實驗的研究則顯示神經性類固醇會影響一些行為作用，例如憂鬱、焦慮、學習與記憶等。目前已知神經性類固醇的生理作用，主要是經由藥理學研究所得到的結果。對於神經性類固醇缺乏在神經系統可能引起之直接效應之相關研究則非常有限。CYP11A1會將膽固醇轉變成孕烯醇酮 (pregnenolone)，為高含量的神經性類固醇之一種，也是其他所有類固醇的前驅物。我們之前產生的Cyp11a1基因剔除鼠會造成小鼠體內類固醇缺乏，我們認為神經性類固醇同樣地無法在神經系統產生。本計畫的目的即利用Cyp11a1基因剔除鼠的動物模式，探討神經性類固醇的生理功能。計畫目標如下：1. 探討Cyp11a1基因在腦的表現分布，並與Cyp11a1基因剔除鼠的結果相比較而加以驗證。2. 探討類固醇缺乏對神經細胞生長的影響。3. 探討神經性類固醇作用之分子機制。4. 探討神經性類固醇對焦慮/憂鬱行為之影響。<br> Abstract: Steroid hormones are primarily produced by the adrenal cortex, gonads and placenta.Besides these classic tissues, neuroactive steroids can be synthesized de novo in the nervous system that are termed neurosteroids. CYP11A1 encodes the first enzyme of steroid biosynthesis, cytochrome P450scc. The expression and activities of the most important steroidogenic enzymes including CYP11A1 have been demonstrated in the nervous system. However, the expression levels of steroidogenic genes in the brain are much lower than that in adrenals and gonads. The localization, transcriptional regulation and physiological significance of most steroidogenic genes in the brain remain to be elucidated.Neurosteroids can exert effects on gene expression through classic steroid hormone nuclear receptors. In general, they mediate their actions through neurotransmitter receptors such as γ-aminobutyric acidA (GABAA) and N-methyl-D-aspartate (NMDA) receptors. Neurosteroids have important effects on neuronal survival, neurogenesis, neurite growth, and myelin formation. Animal and human studies suggested that neuroactive steroids are involved in several behavior processes including depression, anxiety, learning and memory.Most of the physiological functions of neurosteroids in the nervous system are described by pharmacological studies. However, the analysis of direct effects of neurosteriod deficiency in the nervous system is lacking. CYP11A1 converts cholesterol into pregnenolone that is one of the most abundant neurosteroids and also acts as the precursor of all steroids. We previously generated a Cyp11a1 mutant mouse strain and found that steroid synthesis is deficient in this animal. We considered that similarly neurosteroids would not be synthesized in the brain. Therefore, the purpose of this grant proposal is to utilize the Cyp11a1 null (Cyp11a1-/-) mice model to investigate the potential function of neurosteroids in the brain. The specific aims of this proposal are:1. To determine the expression of Cyp11a1 in the brain and compare with that of Cyp11a1-/- mice2. To study effects of steroid-deficiency on neuronal growth in the developing brain3. To study the molecular mechanisms underlying neurosteroid action in the developing brain4. To study the role of neusteroids in the anxiety- and depression-related behaviors by Cyp11a1+/- heterozygous mice膽固醇側鏈截切酶神經性類固醇視網膜凋亡腎上腺皮質固醇補充Cyp11a1neurosteroidretinaapoptosiscorticosteroid rescue