Raloxifene-based therapy in neuro degenerative diseases

基于雷洛昔芬的神经退行性疾病治疗

基本信息

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
项目类别：
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

项目摘要

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.

许多神经退行性疾病，包括 ALS，都以线粒体功能障碍和缺陷为特征在泛素-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与其他组织相比尚不清楚。此外，一些中枢神经系统相关疾病显示出性别差异，但是，同样，这一观察结果的机制来源尚不清楚。当前的应用程序解决了中枢神经系统对蛋白质稳态、线粒体缺陷和性别差异的敏感性增加。日尔曼集团首先描述了雌激素受体α（ERa）驱动的线粒体轴未折叠蛋白反应 (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 实验室在家族性 ALS（一种男性比女性发病更早的模型。我们发现女性保持着这样的能力激活 UPRmt 的 ER 轴比男性长。这些观察结果提出了干预措施的可能性旨在在病程早期激活 UPRmt 的 ERa 轴可能会延缓 ALS 的进展以及其他潜在的中枢神经系统相关疾病。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调节多个水平的蛋白酶体活性和线粒体基因的表达。更远，我们发现雷洛昔芬在该模型中延迟了疾病进展，特别是在女性中，尽管事实上我们的试验中达到的血清水平比人类临床上可能达到的水平低 10 倍长期用雷洛昔芬治疗。这表明雷洛昔芬的独特之处在于其显着的增加与影响脊髓的疾病相关的两个关键途径，例如 ALS，以及可能的其他疾病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达到的水平与人类的治疗方案可以在小鼠身上实现一样，雷洛昔芬的保护作用可以大大提高。基于根据这些结果，我们提出以下三个具体目标。目标 1：了解其分子基础雌激素、他莫昔芬和雷洛昔芬对脊髓 ER 转录活性的不同影响并扩展其对中枢神经系统其他部分影响的分析。目标 2：单独优化雷洛昔芬给药或与蛋白酶体激活剂橄榄苦苷结合使用，扩大对男性的有益作用。目标 3：将基于雷洛昔芬的治疗扩展到 ALS/FTD 突变 Ubiquilin2 小鼠模型。拟议的方案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。作为成千上万的美国人患有这种毁灭性的疾病，而且没有有效的治疗方法，我们认为所提出的雄心勃勃的方法是有充分理由的。