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女性与男性比例显着的原因仍然未知。 在本申请中，我们提出评估一种新想法的可行性，即SLE中的性激素参与处于接近雄激素产生的阶段。我们将检验SLE女性循环中的双烯醇酮水平较低的假设。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、卵巢和睾丸中类固醇激素生物合成途径中非常重要的化合物，因为它是导致孕酮、雄激素和雌激素形成的分支点。由于在女性中，卵巢负责约60%的总产量的双烯醇酮，相比之下，只有30%的双烯醇酮产生的睾丸在男性中，在双烯醇酮的卵巢生产或其生物利用度的缺陷可能会提供洞察女性占主导地位的SLE。 此外，我们假设，用孕烯醇酮可以更有效地实现对疾病发展的控制，而没有目前正在临床试验中的更远端雄激素前体如DHEA所遇到的潜在问题和副作用。我们建议在一个完善的SLE动物模型中测试这种治疗方法的可行性。这些研究的结果将为了解性类固醇在这种疾病中的作用提供一个新的方向，并为人类SLE的治疗提供一种新的方法。 该应用程序结合了自身免疫性疾病生物学（雅各布博士）的专业知识，生殖内分泌学（斯坦奇克博士）和类固醇激素生物化学（罗伯茨博士）的专业知识。拟定项目与PI和其他研究者正在进行的研究存在明显差异。

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.