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: 10535475
• 负责人: DORIS A GERMAIN
• 金额: $ 36.73万
• 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/10535475
• 关键词: Address; Affect; American; Amyotrophic Lateral Sclerosis; Binding Sites; Brain; Breast Cancer Prevention; Central Nervous System; ChIP-seq; Chronic; Clinical; Complex; Cytosol; DNA Binding; Data; Defect; 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; 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; 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; synergism; transcriptome sequencing; ubiquilin; ubiquitin isopeptidase

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.

包括肌萎缩侧索硬化症在内的许多神经退行性疾病的特点是线粒体功能障碍和缺陷。 在泛素-蛋白酶体途径中。然而，为什么中枢神经系统更容易出现这些缺陷 比其他组织更多的是未知的。此外，几种与中枢神经系统相关的疾病显示出性别差异， 同样，这种观察的机制来源尚不清楚。当前应用程序既解决了 中枢神经系统对蛋白质平衡、线粒体缺陷和性别差异的敏感性增加。日耳曼集团 首次描述了雌激素受体α(Era)驱动的线粒体轴未折叠蛋白的反应 (UPRmt)，它促进蛋白酶体的活性，以及线粒体基因的转录。更多 最近，Germain和Manfredi实验室在家族性ALS的SOD1-G93A模型中描述了这一途径，a 男性比女性发病更早的模型。我们发现，女性保持着 激活UPRmt的ER轴的时间比男性长。这些观察结果增加了干预措施 在病程早期激活UPRmt的ERA轴可能会延缓ALS的进展 可能还有其他与中枢神经系统相关的疾病。本申请中提供的数据表明，治疗 使用FDA批准的选择性雌激素调节剂(SERM)雷洛昔芬，但不使用雌激素或他莫昔芬。 在多个水平上调节蛋白酶体活性和线粒体基因的表达。此外， 我们发现，在这个模型中，雷洛昔芬延缓了疾病的进展，特别是在女性身上，尽管事实是 在我们的试验中达到的血清水平比在人类临床上可能达到的水平低10倍。 长期使用雷洛昔芬治疗。这表明雷洛昔芬的独特之处在于它能显著提高 与影响脊髓的疾病相关的两个关键通路，如ALS，以及可能的其他 中枢神经系统的组成部分。此外，我们的研究结果还表明，如果雷洛昔芬的水平接近于 雷洛昔芬在小鼠体内可实现人为给药方案，可大大提高其保护作用。基座 根据这些结果，我们提出了以下三个具体目标。目标1：了解病毒的分子基础 雌激素、三苯氧胺和雷洛昔芬对脊髓ER转录活性的不同影响 并扩展了对其对中枢神经系统其他部分影响的分析。目标2：单独优化雷洛昔芬的释放 或与蛋白酶体激活剂oluropein联合使用，将有益效果扩展到男性。目标3： 将基于雷洛昔芬的治疗扩展到ALS/FTD的突变泛素2小鼠模型。该计划建议 这是一项积极而雄心勃勃的尝试，旨在测试雷洛昔芬对ALS的神经保护作用。AS 数以千计的美国人患有这种毁灭性的疾病，没有有效的治疗方法，我们觉得 提出雄心勃勃的方法是有充分理由的。