Treatment of Multiple Sclerosis with Sex Hormones

描述(由申请人提供)：这个K24奖项的申请旨在为PI提供时间和资源来扩大她的临床研究努力，并在这一努力中指导受训人员。在过去的十年里，Voskuhl博士的实验室在多发性硬化症(MS)动物模型中取得了与性激素治疗相关的核心发现。基于这些发现，她设计并获得了一项小型试点临床试验的资金，然后是一项大型多中心、双盲、安慰剂对照临床试验，用于使用雌三醇片治疗多发性硬化症女性。这些试验试图重述妊娠晚期高水平雌三醇的保护作用，妊娠晚期是MS复发的相对保护期。目的1将通过确定雌三醇治疗是否诱导受试者外周血免疫细胞(PBMC)产生神经保护性生长因子来研究这项多中心试验中的免疫机制。它还将评估雌三醇治疗是否降低了PBMCs中的基质金属蛋白酶，还是增加了CD4+CD25+抑制T细胞。Voskuhl博士还刚刚完成了一项针对男性多发性硬化症患者的试验性临床试验，使用睾丸素凝胶进行治疗。这篇文章试图重述高水平的睾丸素对年轻男性的保护作用。目标1将为PI提供时间和资源，以设计后续的、更大规模、多中心、双盲、安慰剂对照的临床试验，使用睾酮治疗男性多发性硬化症。它还将使用最近完成的睾酮试点试验中提供的PBMCs来确定睾酮治疗是否诱导PBMCs产生神经保护性生长因子。在这个K24奖项中，Voskuhl博士将在临床免疫学研究和临床试验设计方面指导受训人员。这些研究将共同评估针对性别的性激素治疗在多发性硬化症中的疗效和机制。如果性激素治疗被证明能诱导免疫细胞产生神经营养因子，这不仅对多发性硬化症，而且对其他神经退行性疾病也有影响。如果性激素治疗被证明下调基质金属蛋白酶，增加CD4+CD25+抑制T细胞，这不仅对MS，而且对其他细胞介导的自身免疫性疾病都有意义。

DESCRIPTION (provided by applicant): This K24 Award application is designed to provide the PI with the time and resources to expand her clinical research efforts and to mentor trainees in this endeavor. In the past decade, Dr. Voskuhl's laboratory has made central findings related to sex hormone treatment in the animal model of multiple sclerosis (MS). Based on these findings, she designed and gained funding for a small pilot clinical trial, then a large multicenter, double-blind, placebo-controlled clinical trial, to treat women with MS using estriol pills. These trials attempt to recapitulate the protective effect of high levels of estriol during late pregnancy, with late pregnancy being a known time of relative protection from MS relapses. Aim 1 will examine immune mechanisms during this multicenter trial by determining whether estriol treatment induces neuroprotective growth factor production by peripheral blood immune cells (PBMCs) derived from subjects in this trial. It will also assess whether estriol treatment decreases matrix metalloproteinases in PBMCs or increases CD4+CD25+ suppressor T cells. Dr. Voskuhl has also just completed a pilot clinical trial in men with MS using treatment with a testosterone gel. This attempts to recapitulate the protective effect of high testosterone levels in young men. Aim 1 will provide the time and resources for the PI to design the follow up, larger, multicenter, double- blind, placebo-controlled clinical trial to treat men with MS using testosterone. It will also use PBMCs available from the recently completed testosterone pilot trial to determine whether testosterone treatment induces neuroprotective growth factor production by PBMCs. In this K24 Award, Dr. Voskuhl will mentor trainees in clinical immunology studies as well as in clinical trial design. Together these studies will assess the efficacy and mechanism of gender tailored sex hormone treatments in MS. If treatment with sex hormones is shown to induce neurotrophic factor production by immune cells, this would have implications for not only for MS, but also for other neurodegenerative diseases. If treatment with sex hormones is shown to down-regulate matrix matalloproteinases and increase CD4+CD25+ suppressor T cells, this would have implications for not only MS, but also for other cell mediated autoimmune diseases.