A novel estrogen modulator for the treatment of Alzheimer's disease

一种用于治疗阿尔茨海默病的新型雌激素调节剂

基本信息

批准号：
9898288
负责人：
JOSEPH F QUINN
金额：
--
依托单位：
PORTLAND VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9898288
关键词：
Adverse effects Affect Age Age-associated memory impairment Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Amyloid beta-Protein Amyloidosis Animals Anti-Inflammatory Agents Antioxidants Attenuated Biochemical Biochemical Markers Biological Assay Biological Models Blood Coagulation Factor Blood coagulation Brain Cell Culture Techniques Cells Clinical Clinical Trials Coagulation Process Data Enzyme-Linked Immunosorbent Assay Estrogens Evaluation Event Feminization Future Genetic Engineering Genetically Engineered Mouse Goals Gonadal Steroid Hormones Healthcare Systems Hippocampus (Brain)Histologic Hormones Human Immunohistochemistry Inbred C57BL Mice Investigation Laboratories Lesion Malignant Neoplasms Measurement Mediating Memory Methods Mitochondria Molecular Morbidity - disease rate Morphology Mus Mutation Neurons Oncogenic Ovariectomy Pathway interactions Patients Pharmaceutical Preparations Pharmacology Postmenopause Prevention Prevention therapy Property Protocols documentation RNA Interference Reverse Transcriptase Polymerase Chain Reaction Risk Role Safety Series Signal Pathway Signal Transduction Synapses Testing Tg2576 Transgenic Mice Transgenic Organisms Validation Vertebral column Wild Type Mouse Woman aging brain base behavior test clinical development cost density estrogenic experimental study human subject in vivo inhibitor/antagonist interest male men metal chelator morris water maze mouse model neuroprotection neurotoxic neurotoxicity normal aging novel novel therapeutics prevent protective effect protein aggregation reproductive organ response side effect spatial memory

项目摘要

A number of studies have shown that the sex hormone, estrogen, has favorable or “neurotrophic” effects on neuronal cells in the brain. Unfortunately, clinical trials using estrogen revealed unacceptable side effects, including increased risk of blood clots and hormone- sensitive cancers. Moreover, estrogen is not practical for use in men, because it promotes unwanted physical changes and feminizing effects; consequently, estrogen has been abandoned as a treatment for AD. As an alterative strategy, the current study will test a novel drug called “STX”, which has the favorable neurotrophic effects of estrogen without its unwanted side effects. Preliminary studies indicate that STX protects neuronal cells against Alzheimer’s-associated toxic responses and can be safely given to mice as they age. The overall goal is to determine if STX has potential for treating Alzheimer’s disease in human patients. This drug will be tested first on brain neuronal cells grown in a dish under conditions that mimic specific aspects of Alzheimer’s disease, with the goal of identifying the molecular pathways that control its protective responses. The drug will then will be tested in normal aging mice (to confirm its safety), and in mice that have been genetically engineered to develop Alzheimer-type changes in the brain. Established protocols will be used to carefully assess the effects of STX on memory function, neuronal damage, and brain lesions associated with Alzheimer’ Disease. These studies will integrate behavioral tests of spatial memory, immunohistochemical methods to quantify neuronal damage, and biochemical assays to quantify protein aggregation. Concurrently, the molecular pathways identified in cultured neuronal cells will be validated in the brains of treated animals. Successful completion of these experiments will provide the framework for advancing STX toward clinical trials.

许多研究表明，性激素雌激素具有有利或有利的作用。不幸的是，临床试验使用雌激素对大脑神经元细胞产生“神经营养”作用。揭示了不可接受的副作用，包括血栓和激素风险增加此外，雌激素不适用于男性，因为它会促进癌症的发生。因此，雌激素会带来不良的身体变化和女性化效应；被放弃作为 AD 的治疗方法。作为一种替代策略，当前的研究将测试一种名为“STX”的新药，该药物具有雌激素具有良好的神经营养作用，且没有不良副作用。表明 STX 可以保护神经细胞免受阿尔茨海默病相关的毒性反应，并且随着小鼠年龄的增长，可以安全地给予它们，总体目标是确定 STX 是否具有潜力。用于治疗人类患者的阿尔茨海默病。该药物将首先在模拟条件下在培养皿中生长的脑神经元细胞上进行测试阿尔茨海默氏病的具体方面，目的是确定导致阿尔茨海默氏病的分子途径然后将在正常衰老小鼠中测试该药物的保护性反应（以确认其安全性），以及经过基因工程改造而患有阿尔茨海默病的小鼠已制定的方案将用于仔细评估 STX 的影响。与阿尔茨海默病相关的记忆功能、神经元损伤和脑损伤。这些研究将整合空间记忆的行为测试、免疫组织化学方法量化神经元损伤，以及量化蛋白质聚集的生化测定。同时，在培养的神经细胞中确定的分子途径将在成功完成这些实验将提供经过治疗的动物的大脑。推进 STX 走向临床试验的框架。