权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Discovery of functionally selective Alzheimer's disease therapeutics

发现功能选择性阿尔茨海默病疗法

基本信息

批准号：
9754738
负责人：
ROBERT R LUEDTKE
金额：
$ 54.46万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9754738
关键词：
APP-PS1 Activities of Daily Living Address Adrenergic Agents Affinity Alzheimer&apos s Disease Alzheimer&apos s disease model Amyloid Amyloid beta-Protein Behavioral Biological Assay Biological Markers Brain Brain-Derived Neurotrophic Factor CYP2D6 gene CYP3A4 gene Caregiver Burden Caring Cells Chronic Cognitive Cognitive deficits Dementia Deposition Development Development Plans Disease Disease Progression Dopamine Dopamine D2 Receptor Dose Drug Interactions Encephalitis Evaluation Family Financial Hardship Friends Future Generations Goals Half-Life Haloperidol Histologic Hour Hydrogen Peroxide Impairment Inflammation Inflammatory Interruption Lead Liver Microsomes Measurable Measures Mediating Medical Medicare Medicine Memory Metabolic Modeling Molecular Chaperones Mus Muscarinic Acetylcholine Receptor Nerve Degeneration Neuroglia Neurons Nitrates Nitric Oxide Oral Oral Administration Oxidative Stress Parents Pathogenicity Pathology Patients Peroxonitrite Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacotherapy Plasma Prevalence Primates Process Property Proteins Purinergic P1 Receptors Recovery Research Rodent Selection Criteria Serotonin Stress Superoxides Symptoms Synapses Therapeutic Toxic effect Transgenic Mice United States abeta deposition abeta oligomer age related base behavior test cannabinoid receptor cerebral atrophy cognitive performance cytotoxic dose information drug development drug testing entorhinal cortex hyperphosphorylated tau improved in vivo innovation lead candidate mild cognitive impairment mouse model neuroinflammation nitration nitrosative stress non-drug prevent progressive neurodegeneration protein biomarkers receptor resilience screening sigma-1 receptor tau Proteins tau aggregation

项目摘要

Abstract The prevalence of Alzheimer's disease (AD) and the associated financial and caregiver burden is projected to escalate dramatically unless disease-modifying treatments are discovered. Our research is focused on addressing this urgent unmet medical and societal need through the discovery and development of pharmacotherapies capable of averting or delaying the progression of AD. Brain inflammation initiated by chronic oxidative-nitrosative stress is a proven component of the pathogenic cascade leading to mild cognitive impairment (MCI) and AD. When surplus inflammatory nitric oxide and superoxide molecules combine they form the brain-impairing reactive species peroxynitrite. This perpetuates inflammation resulting in the progressive neurodegeneration observed in AD. Our innovative approach consists of managing two processes associated with inflammatory disease progression. The first involves interrupting the cycle of peroxynitrite generation by suppressing unsafe elevations in nitric oxide triggered by oxidative stress, and the second involves enhancing resilience to and recovery from inflammatory insults by facilitating the secretion of brain-derived neurotrophic factor (BDNF). A single stress-activated chaperone protein is mechanistically capable of both mediating BDNF secretion and regulating nitric oxide levels under proinflammatory conditions. Preliminary studies have identified chemotype starting points for further CNS drug development which have the desired dual functional selectivity profile for this target receptor. Our plan is to optimize the CNS drug-like properties of these functionally selective chemotypes with the goal of developing medicines that can significantly modify the course of MCI/AD.

摘要