Treatment of Multiple Sclerosis with Sex Hormones

描述（由申请人提供）：此K24奖申请旨在为PI提供时间和资源，以扩大她的临床研究工作，并指导学员在这奋进的努力。在过去的十年中，Voskuhl博士的实验室在多发性硬化症（MS）的动物模型中取得了与性激素治疗相关的重要发现。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，使用雌三醇药丸治疗MS女性。这些试验试图概括妊娠晚期高水平雌三醇的保护作用，妊娠晚期是相对保护MS复发的已知时间。目的1将通过确定雌三醇治疗是否诱导来自本试验受试者的外周血免疫细胞（PBMC）产生神经保护性生长因子来检查本多中心试验期间的免疫机制。还将评估雌三醇治疗是否降低PBMC中的基质金属蛋白酶或增加CD4+CD25+抑制性T细胞。Voskuhl博士还刚刚完成了一项使用睾酮凝胶治疗MS男性的试点临床试验。这试图概括高睾丸激素水平对年轻男性的保护作用。目的1将为PI设计使用睾酮治疗MS男性的随访、更大规模、多中心、双盲、安慰剂对照临床试验提供时间和资源。它还将使用从最近完成的睾酮试点试验中获得的PBMC来确定睾酮治疗是否诱导PBMC产生神经保护性生长因子。在这个K24奖中，Voskuhl博士将指导临床免疫学研究和临床试验设计的学员。这些研究将共同评估MS中性别定制性激素治疗的疗效和机制。如果性激素治疗显示出诱导免疫细胞产生神经营养因子，这将不仅对MS有影响，而且对其他神经退行性疾病也有影响。如果用性激素治疗显示下调基质金属蛋白酶和增加CD4+CD25+抑制性T细胞，这将不仅对MS，而且对其他细胞介导的自身免疫性疾病有影响。

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.