Raloxifene-based therapy in neuro degenerative diseases

基于雷洛昔芬的神经退行性疾病治疗

• 批准号: 10307584
• 负责人: DORIS A GERMAIN
• 金额: $ 26.94万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10307584
• 关键词: Address; Affect; American; Amyotrophic Lateral Sclerosis; Binding Sites; Brain; Breast Cancer Prevention; ChIP-seq; Chronic; Clinical; Complex; Cytosol; DNA Binding; Data; Defect; Degenerative Disorder; Deubiquitinating Enzyme; Disease; Disease Progression; Dose; Estrogen Receptor alpha; Estrogen Therapy; Estrogens; FDA approved; Female; Gene Expression; Genes; Genetic Transcription; Homeostasis; Human; Intervention; Mitochondria; Modeling; Molecular; Mus; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Onset of illness; Osteoporosis prevention; Pathway interactions; Patients; Phase; Predisposition; Proteasome Inhibition; Proteins; Raloxifene; Regimen; Selective Estrogen Receptor Modulators; Serum; Source; Specificity; Spinal Cord; Stress; Symptoms; Tamoxifen; Testing; Tissues; Ubiquitin; Work; base; effective therapy; familial amyotrophic lateral sclerosis; frontotemporal lobar dementia-amyotrophic lateral sclerosis; gender disparity; improved; improved outcome; male; misfolded protein; mitochondrial dysfunction; mouse model; multicatalytic endopeptidase complex; mutant; mutant mouse model; nervous system disorder; neuroprotection; programs; protective effect; protein aggregation; proteostasis; proteotoxicity; response; sex; sex disparity; sexual dimorphism; sexual disparity; superoxide dismutase 1; transcriptome sequencing; ubiquilin

Many neurodegenerative diseases, including ALS, are characterized by mitochondrial dysfunction and defects in the ubiquitin-proteasome pathway. However, why the central nervous system is more prone to these defects than other tissues is unknown. In addition, several of the CNS-associated diseases show sexual disparity but, again, the mechanistic source of this observation is unclear. The current application addresses both the increased sensitivity of the CNS to proteostasis and mitochondrial defects and sex disparity. The Germain group first described an estrogen receptor alpha (ERa) driven axis of the mitochondria unfolded protein response (UPRmt), which promotes the activity of the proteasome, as well as the transcription of mitochondrial genes. More recently, the Germain and Manfredi labs characterized this pathway in the SOD1-G93A model of familial ALS, a model in which males show earlier disease onset than females. We found that females maintain the ability to activate the ER axis of the UPRmt longer than males. These observations raise the possibility that interventions aimed at activating the ERa axis of the UPRmt early on in the disease course may delay the progression of ALS and potentially other CNS-associated diseases. Data presented in this application demonstrate that treatment with the FDA-approved selective estrogen modulator (SERM) raloxifene, but not estrogen or tamoxifen up- regulates expression of both the activity of the proteasome at multiple levels and mitochondria genes. Further, we found that raloxifene delays disease progression in this model, in females specifically, despite the fact that the serum level achieved in our trial was 10-fold lower than what is possible to achieve clinically in humans treated chronically with raloxifene. This suggests that raloxifene is unique in its remarkable ability to increase two of the key pathways associated with diseases affecting the spinal cord, such as ALS, and possibly other components of the CNS. Moreover, our findings also suggest that if levels of raloxifene closer to those achieved with human regimens can be achieve in mice, the protective effect of raloxifene could be much improved. Based on these results, we propose the three following specific aims. Aim 1: Understanding the molecular basis of the differential effect of estrogen, tamoxifen and raloxifene on the transcriptional activity of the ER in the spinal cord and expand the analysis of their effects on other parts of the CNS. Aim 2: Optimize raloxifene delivery,, alone or in combination with the proteasome activator oleuropein and extend the beneficial effect to males. Aim 3: Extending raloxifene-based therapy to a mutant Ubiquilin2 mouse model of ALS/FTD. The program proposed here is an aggressive and ambitious attempt at testing the neuroprotective effects of raloxifene in ALS. As thousands of Americans suffer from this devastating disease, which has no effective therapy, we feel that the ambitious approaches proposed are well justified.

包括ALS在内的许多神经退行性疾病的特征是线粒体功能障碍和缺陷 在泛素 - 蛋白酶体途径中。但是，为什么中枢神经系统更容易出现这些缺陷 比其他组织未知。此外，几种与中枢神经系统相关的疾病显示出性别差异，但 同样，该观察的机械源尚不清楚。当前的申请都解决了 中枢神经系统对蛋白质的敏感性和线粒体缺陷和性别差异的提高。 Germain组 首先描述了线粒体展开的蛋白质反应的雌激素受体α（ERA）驱动的轴 （UPRMT），促进蛋白酶体的活性以及线粒体基因的转录。更多的 最近，Germain和Manfredi实验室在SOD1-G93A家族ALS模型中表征了这一途径 男性比女性表现出更早的疾病发作的模型。我们发现女性保持 激活UPRMT的ER轴比男性更长。这些观察结果提出了干预措施的可能性 旨在在疾病过程中早期激活UPRMT的时代轴可能会延迟ALS的发展 以及可能与CNS相关的其他疾病。本应用程序中提供的数据表明治疗 与FDA批准的选择性雌激素调节剂（SERM）roxifene一起，但不是雌激素或他莫昔芬 调节蛋白酶体在多个水平和线粒体基因的表达。更远， 我们发现，雷洛昔芬在该模型中，在女性中延迟了疾病的进展，尽管事实是 在我们的试验中达到的血清水平比人类临床实现的可能低10倍 用roxifene长期治疗。这表明拉洛昔芬在其出色的增加能力方面是独一无二的 与影响脊髓的疾病相关的两个关键途径，例如ALS，甚至可能 中枢神经系统的组成部分。此外，我们的发现还表明，如果雷昔芬的水平更接近所达到的水平 在小鼠中可以实现人类方案，可以大大改善雷昔芬的保护作用。基于 在这些结果上，我们提出了以下三个特定目标。目标1：了解分子基础 雌激素，他莫昔芬和雷昔芬对脊髓中ER转录活性的差异作用 并扩展其对中枢神经系统其他部位的影响的分析。 AIM 2：优化兰昔芬递送，单独 或与蛋白酶体活化剂酸蛋白结合使用，并将有益作用扩展到男性。目标3： 将基于rAxifene的治疗扩展到ALS/FTD的突变泛素2小鼠模型。该计划提出了 这是一种积极而雄心勃勃的尝试，试图测试Raloxifene在ALS中的神经保护作用。作为 成千上万的美国人患有这种毁灭性疾病，没有有效的治疗，我们认为 提出的雄心勃勃的方法是有道理的。