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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，有有利的或