A new direction in studing sex hormone involovement in *

描述(由申请人提供)： 系统性红斑狼疮(SLE)和其他自身免疫性疾病中显著的男女比例的原因尚不清楚。在目前的应用中，我们建议评估一个新想法的可行性，即SLE中的性激素参与处于雄激素产生的近端阶段。我们将检验这一假说，即SLE女性体内的孕烯醇酮水平较低。为此，我们将使用最先进的技术来测量这种类固醇激素前体。孕烯醇酮是肾上腺、卵巢和睾丸类固醇激素生物合成途径中非常重要的化合物，因为它是孕酮、雄激素和雌激素形成的分支点。由于在女性中，卵巢约占孕烯醇酮总产量的60%，而男性仅有30%的孕烯醇酮是由睾丸产生的，因此卵巢孕烯醇酮的缺陷或其生物利用度可能有助于了解女性在SLE中的优势。 此外，我们假设孕烯醇酮可以更有效地控制疾病的发展，并且没有更远端的雄激素前体遇到的潜在问题和副作用，例如目前正在进行临床试验的DHEA。我们建议在一个公认的系统性红斑狼疮动物模型中测试这种治疗方法的可行性。这些研究的结果应该会为理解性激素在这种疾病中的作用和人类SLE的新治疗方法提供一个新的方向。该应用程序结合了自身免疫性疾病生物学专业知识(雅各布博士)和生殖内分泌学专业知识(斯坦奇克博士)和类固醇激素生物化学专业知识(罗伯茨博士)。拟议的项目与PI和其他调查人员正在进行的研究有明显和明显的区别。

DESCRIPTION (provided by applicant): The cause for the remarkable female to male ratio in Systemic Lupus Ersthematosus (SLE) and other autoimmune diseases is still unknown. In the present application we propose to evaluate the feasibility of a novel idea, namely that the sex hormonal involvement in SLE is at a stage proximal to the production of androgens. We will test the hypothesis that SLE females have low circulating levels of pregnenolone. To this end we will use state-of-the art techniques for measuring this steroid hormone precursor. Pregnenolone is a very important compound in I the pathway of steroid hormone biosynthesis in the adrenal, ovary and testis because it is the branching point that leads to formation of progesterone, androgens and estrogens. Since in females the ovaries are responsible for approximately 60% of total production of pregnenolone, compared to only 30% of pregnenolone produced by testes in males, a defect in the ovarian production of pregnenolone or its bioavailability might provide insight into female predominance in SLE. In addition, we hypothesize that manipulation of disease development can be achieved with Pregnenolone more efficiently and without the potential problems and side effects encountered by more distal androgen precursors such as DHEA which is presently under clinical trial. We propose to test the feasibility of this therapeutic approach in a well-established animal model of SLE. The results of these studies should lead to a novel direction in understanding the role sex steroids in this disease and to a new therapeutic approach in human SLE. This application combines expertise in autoimmune diseases biology (Dr. Jacob) with expertise in reproductive endocrinology (Dr. Stanczyk) and biochemistry of steroid hormones (Dr. Roberts). The project proposed represents a clear and distinct departure from the PI's and the other investigators ongoing research.