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:
- 金额:$ 26.94万
- 依托单位:
- 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:
- 关键词:AddressAffectAmericanAmyotrophic Lateral SclerosisBinding SitesBrainBreast Cancer PreventionChIP-seqChronicClinicalComplexCytosolDNA BindingDataDefectDegenerative DisorderDeubiquitinating EnzymeDiseaseDisease ProgressionDoseEstrogen Receptor alphaEstrogen TherapyEstrogensFDA approvedFemaleGene ExpressionGenesGenetic TranscriptionHomeostasisHumanInterventionMitochondriaModelingMolecularMusNerve DegenerationNeuraxisNeurodegenerative DisordersOnset of illnessOsteoporosis preventionPathway interactionsPatientsPhasePredispositionProteasome InhibitionProteinsRaloxifeneRegimenSelective Estrogen Receptor ModulatorsSerumSourceSpecificitySpinal CordStressSymptomsTamoxifenTestingTissuesUbiquitinWorkbaseeffective therapyfamilial amyotrophic lateral sclerosisfrontotemporal lobar dementia-amyotrophic lateral sclerosisgender disparityimprovedimproved outcomemalemisfolded proteinmitochondrial dysfunctionmouse modelmulticatalytic endopeptidase complexmutantmutant mouse modelnervous system disorderneuroprotectionprogramsprotective effectprotein aggregationproteostasisproteotoxicityresponsesexsex disparitysexual dimorphismsexual disparitysuperoxide dismutase 1transcriptome sequencingubiquilin
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.
包括ALS在内的许多神经退行性疾病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。但是,为什么中枢神经系统更容易出现这些缺陷呢
比其他组织更好的是未知的。此外,几种CNS相关疾病显示出性别差异,
同样,这一观察结果的机制来源也不清楚。当前的应用程序解决了
CNS对蛋白质稳态和线粒体缺陷以及性别差异的敏感性增加。Germain集团
首先描述了雌激素受体α(ER α)驱动的线粒体未折叠蛋白反应轴
(UPRmt),其促进蛋白酶体的活性以及线粒体基因的转录。更
最近,Germain和Manfredi实验室在家族性ALS的SOD 1-G93 A模型中表征了这一通路,
男性比女性更早发病的模型。我们发现雌性保持着
激活UPRmt的ER轴的时间比男性长。这些观察结果提出了干预措施
在病程早期激活UPRmt的ER α轴可能延缓ALS的进展
以及其他潜在的CNS相关疾病。本申请中提供的数据表明,
与FDA批准的选择性雌激素调节剂(SERM)雷洛昔芬,但不是雌激素或他莫昔芬-
在多个水平调节蛋白酶体的活性和线粒体基因的表达。此外,本发明还
我们发现,雷洛昔芬在该模型中延迟疾病进展,特别是在女性中,尽管事实上,
在我们的试验中达到的血清水平比临床上可能达到的人类水平低10倍
用雷洛昔芬长期治疗。这表明,雷洛昔芬是独特的,其显着的能力,增加
与影响脊髓的疾病相关的两个关键途径,如ALS,以及可能的其他
CNS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所达到的水平,
与人类方案可以在小鼠中实现,雷洛昔芬的保护作用可以大大提高。基于
根据这些结果,我们提出了以下三个具体目标。目标1:了解
雌激素、他莫昔芬和雷洛昔芬对脊髓中ER转录活性的不同影响
并扩大其对中枢神经系统其他部分的影响的分析。目的2:优化雷洛昔芬单独给药
或与蛋白酶体激活剂橄榄苦苷组合,并将有益效果扩展至男性。目标三:
将基于雷洛昔芬的治疗扩展至ALS/FTD的突变Ubiquilin 2小鼠模型。该方案提出,
这是一项雄心勃勃的尝试,旨在测试雷洛昔芬在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的疾病,没有有效的治疗方法,我们认为,
提出的雄心勃勃的办法是有充分理由的。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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DORIS A GERMAIN其他文献
DORIS A GERMAIN的其他文献
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{{ truncateString('DORIS A GERMAIN', 18)}}的其他基金
Exploring ovarian-derived hormone STC1 as the mediator of the protective effect of breast feeding against breast cancer.
探索卵巢源性激素 STC1 作为母乳喂养对乳腺癌保护作用的中介。
- 批准号:
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- 资助金额:
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Understanding the influence of Mitochondrial DNA haplotypes on breast aging and cancer
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- 批准号:
10591676 - 财政年份:2023
- 资助金额:
$ 26.94万 - 项目类别:
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:
10532927 - 财政年份:2020
- 资助金额:
$ 26.94万 - 项目类别:
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 - 财政年份:2020
- 资助金额:
$ 26.94万 - 项目类别:
The role of the mitochondrial unfolded protein response (UPRmt) in the etiology of breast cancer in young versus elderly women.
线粒体未折叠蛋白反应 (UPRmt) 在年轻与老年女性乳腺癌病因学中的作用。
- 批准号:
9927550 - 财政年份:2019
- 资助金额:
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Exploring the use of conplastic mice as a model of risk stratification of coronavirus susceptibility
探索使用再生小鼠作为冠状病毒易感性风险分层模型
- 批准号:
10162776 - 财政年份:2018
- 资助金额:
$ 26.94万 - 项目类别:
Understanding the role of mitochondrial UPR-activating mtDNA landscapes in health and longevity.
了解线粒体 UPR 激活 mtDNA 景观在健康和长寿中的作用。
- 批准号:
10172817 - 财政年份:2018
- 资助金额:
$ 26.94万 - 项目类别:
Understanding the role of mitochondrial UPR-activating mtDNA landscapes in health and longevity.
了解线粒体 UPR 激活 mtDNA 景观在健康和长寿中的作用。
- 批准号:
9923529 - 财政年份:2018
- 资助金额:
$ 26.94万 - 项目类别:
Understanding the role of mitochondrial UPR-activating mtDNA landscapes in health and longevity.
了解线粒体 UPR 激活 mtDNA 景观在健康和长寿中的作用。
- 批准号:
10417179 - 财政年份:2018
- 资助金额:
$ 26.94万 - 项目类别:
Understanding the role of mitochondrial UPR-activating mtDNA landscapes in health and longevity.
了解线粒体 UPR 激活 mtDNA 景观在健康和长寿中的作用。
- 批准号:
9752438 - 财政年份:2018
- 资助金额:
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