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.

抽象的阿尔茨海默氏病（AD）的患病率以及相关的财务和照料者负担预计将升级除非发现疾病改良治疗，否则很大。我们的研究重点是解决这一紧急情况通过发现和开发能够避免或延迟的药物治疗，医疗和社会需求 AD的进展。慢性氧化亚硝化应激引发的脑炎症是事实的成分致病性级联反应导致轻度认知障碍（MCI）和AD。当多余的炎症一氧化氮和超氧化物分子结合在一起，它们形成了脑损伤的反应性物种过氧氮。这是永久的炎症导致在AD中观察到的进行性神经退行性变化。我们的创新方法包括管理与炎症性疾病进展相关的两个过程。第一个涉及中断过氧亚硝酸盐通过抑制由氧化应激触发的一氧化氮的不安全升高而产生的，第二个涉及通过促进脑源性的分泌来增强对炎症侮辱的弹性和恢复神经营养因子（BDNF）。单个应力激活的伴侣蛋白在机械上能够介导在促炎条件下，BDNF分泌和调节一氧化氮水平。初步研究已经确定进一步的CNS药物开发的化学型起点，具有所需的双功能选择性曲线该靶受体。我们的计划是优化这些功能选择性化学型的CNS药物样性能开发可以显着修改MCI/AD进程的药物的目标。