Sigma-1 Receptors: A Novel Clinical Target in Fragile X Syndrome

Sigma-1 受体：脆性 X 综合征的新临床靶点

• 批准号: 9923000
• 负责人: Guido Alejandro Davidzon
• 金额: $ 19.56万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2021-05-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9923000
• 关键词: Adult; Affect; Age; Akathisia; American; Anterior; Antidepressive Agents; Antipsychotic Agents; Area; Basal Ganglia; Behavior Therapy; Behavioral; Benzodiazepines; Biological Markers; Biology; Brain; Cell physiology; Cell surface; Cerebellum; Clinical; Clinical Research; Cognition; Cognitive; Complex; Development; Developmental Delay Disorders; Diagnosis; Discipline; Disease; Emotional; Endoplasmic Reticulum; Executive Dysfunction; Family; Foundations; Fragile X Syndrome; Functional disorder; Genes; Goals; Impairment; Increased sweating; Individual; Inherited; Intellectual functioning disability; Ion Channel; Lateral Geniculate Body; Learning; Lethargies; Life; Ligands; Longevity; Magnetic Resonance Imaging; Measures; Mediating; Memory; Methods; Molecular; Molecular Chaperones; Monitor; Mood stabilizers; Multimodal Imaging; Mutation; N-Methyl-D-Aspartate Receptors; Nausea; Neurobiology; Neuroprotective Agents; Neuropsychology; Neurotransmitters; Patients; Pharmacological Treatment; Pharmacology; Phenotype; Play; Positron-Emission Tomography; Prefrontal Cortex; Quality of life; Reproducibility; Research; Research Personnel; Rodent; Role; Severities; Social Development; Societies; Supportive care; System; Tachycardia; Testing; Therapeutic; Translating; Visuospatial; Weight Gain; area striata; autism spectrum disorder; base; brain behavior; cell growth regulation; cingulate cortex; cognitive ability; cognitive function; cognitive skill; companion diagnostics; density; design; differential expression; executive function; functional disability; human subject; imaging agent; imaging approach; imaging probe; improved; interest; kinetic model; male; molecular imaging; neurodevelopment; neurogenetics; neuronal survival; neuropsychiatry; neurotransmitter release; nonhuman primate; novel; outcome forecast; radioligand; radiotracer; receptor; receptor expression; relating to nervous system; side effect; sigma-1 receptor; skill acquisition; symptom treatment; synaptogenesis; targeted treatment; therapeutic biomarker; treatment response; uptake; young adult

SUMMARY: Fragile X syndrome is a debilitating neurogenetic disorder that can result in a multitude of impairments in cognition, memory, and learning. Maladaptive functioning in socio-emotional, cognitive and behavioral domains greatly hinder educational and social development resulting in dysfunction that persists into adulthood. Currently, pharmacological agents such as antipsychotics, antidepressants, and mood stabilizers are recommended in conjunction with behavioral intervention and are focused on symptomatic treatment. In addition to having significant side effects, long term use of these agents can further impede cognitive ability. Therefore, targeted pharmacological treatment is crucial to mitigate these challenges and facilitate optimal development. Recent evidence has brought forth sigma-1 receptor ligands (S1R) as a potential new class of neuroprotective agents. Sigma-1 receptors (S1R) are widely distributed throughout the brain where they interact with ion channels and neurotransmitters and play a critical role in the function of cognition, learning and memory. In this proposal, we will employ our S1R-selective imaging agent, 18F-FTC-146, with positron emission tomography (PET) to begin understanding the functional role of S1Rs in males with FXS. We will translate and explore the utility of clinical- grade 18F-FTC-146 PET-MR imaging to investigate S1R density in males with FXS. Thus, we hypothesize that PET-MR imaging with our highly selective S1R radioligand (18F-FTC-146) will be a useful strategy for studying the potential role of S1Rs for treating FXS. Our imaging approach, utilizing PET and MR imaging, promises to aid clinicians to better develop and select targeted treatments and monitoring treatment response. In addition, it will benefit researchers in multiple disciplines studying the pathophysiology and treatment of FXS and can significantly improve quality of life for families and individuals with intellectual disabilities.

总结： 脆性X染色体综合征是一种使人衰弱的神经遗传性疾病，可导致多种功能障碍， 认知、记忆和学习。社会情绪、认知和行为领域的适应不良功能 严重阻碍教育和社会发展，导致功能障碍，持续到成年。目前， 推荐使用抗精神病药、抗抑郁药和情绪稳定剂等药物， 与行为干预相结合，并侧重于对症治疗。除了具有 尽管这些药物具有显著的副作用，但长期使用这些药物可进一步阻碍认知能力。因此，针对 药物治疗对于缓解这些挑战和促进最佳发育至关重要。最近 有证据表明sigma-1受体配体（S1 R）是一类潜在的新型神经保护剂。 σ-1受体（S1 R）广泛分布于整个大脑，在那里它们与离子通道相互作用， 神经递质，并在认知，学习和记忆功能中发挥关键作用。在本提案中，我们 将使用我们的S1 R选择性显像剂18 F-FTC-146，与正电子发射断层扫描（PET）一起开始 了解S1 R在男性FXS患者中的功能作用。我们将翻译和探索临床的效用- 18级F-FTC-146 PET-MR成像，以研究FXS男性患者的S1 R密度。因此，我们假设， 使用我们的高选择性S1 R放射性配体（18F-FTC-146）进行PET-MR成像将是研究 S1 R在治疗FXS中的潜在作用。我们的成像方法，利用PET和MR成像，承诺 帮助临床医生更好地开发和选择靶向治疗并监测治疗反应。此外还 将有利于研究FXS病理生理学和治疗的多学科研究人员， 显著改善智障家庭和个人的生活质量。