Administrative Core

行政核心

• 批准号: 10398387
• 负责人: JOSHUA J.C. ROSENTHAL
• 金额: $ 66.65万
• 依托单位: MARINE BIOLOGICAL LABORATORY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-23 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398387
• 关键词: Address; Adenosine; Adult; Affect; Afferent Neurons; Amino Acids; Analgesics; Animal Model; Animal Testing; Architecture; Area; Arginine; Award; BCAR1 gene; Base Pairing; Biological; Biology; Budgets; Cardiac; Cells; Charge; Clinical Trials; Codon Nucleotides; Communication; Conflict (Psychology); Consensus; Core Facility; DNA; Data; Data Analyses; Development; Diabetes Mellitus; Disease model; Effectiveness; Electrophysiology (science); Elements; Ensure; Enzymes; Evaluation Research; FDA approved; Financial Support; Funding; Genetic; Geography; Goals; Grant; Guanosine; Guide RNA; Guidelines; Heart Diseases; Human; Inosine; Institution; Intellectual Property; Ions; Laboratories; Lead; Legal; Logistics; Lysine; Malignant - descriptor; Malignant Neoplasms; Messenger RNA; Modification; Monitor; Motion; Neurons; Overdose; Pain; Pain Disorder; Patients; Peripheral; Permeability; Pharmaceutical Preparations; Prevalence; Progress Reports; Property; Property Rights; Protein Isoforms; RNA; RNA Editing; Reagent; Regulation; Reporting; Research; Research Priority; Research Support; Resource Sharing; Resources; Services; Shunt Device; Site; Sodium Channel; Structure; Supervision; System; Texas; Time; TimeLine; United States National Institutes of Health; Universities; Work; Workplace; addiction; arm; base; channel blockers; chronic pain; commercialization; conflict resolution; data management; disability; dsRNA adenosine deaminase; experience; immunogenic; meetings; member; novel; opioid abuse; pain model; programs; side effect; small molecule; success; targeted treatment; voltage

Chronic pain is a leading cause of disability, affecting about one-third of adults worldwide, with a prevalence greater than heart disease, cancer, and diabetes combined. Misuse and abuse of opiates have led to a nationwide addiction and overdose crisis. Thus, there is an urgent need for alternative, non-addictive analgesics. Non-selective voltage-gated sodium channel (Nav) blockers are among existing non-addictive FDA-approved drugs which can sometimes provide symptomatic relief for patients. However, their utility is limited by CNS and cardiac side effects. Genetic and functional studies of human pain disorders and animal models of pain have validated NaV1.7, a voltage-gated Na Channel that is preferentially expressed in peripheral neurons, as an attractive target for therapy. Isoform-selective Nav blockers, however, are difficult to generate and those that have been generated are rapidly cleared from the body, limiting their effectiveness. Alternative approaches are needed. We propose a novel, non-addictive approach to treat chronic pain by editing the messages that encode NaV1.7 in order to alter its electrophysiological properties. By changing a single lysine codon to arginine in the ion selectivity filter, the channel will go from being Na+ selective to both Na+ and K+ selective, effectively creating a counter-current shunt that will dampen excitability. Site-Directed RNA Editing (SDRE) refers to novel mechanisms to generate programmed edits within RNAs. It relies on the ADAR (Adenosine Deaminase that Acts on RNA) enzymes, which are endogenously expressed in human cells, including sensory neurons. Directed by a guide RNA (gRNA), SDRE systems convert precisely selected adenosines to inosine, a translational mimic for guanosine, which can recode specific amino acids. For use as an analgesic, editing mRNA is preferable to DNA because it is transient, thus limiting potential off-target effects, including malignant transformations and ADARs are endogenous while enzymes for DNA manipulation (e.g. Cas proteins) are not, thus SDRE will not be as immunogenic. Compared to small molecule channel blockers, SDRE can be more specific, because it relies on Watson-Crick base-pairing of gRNAs for targeting, and its effects are likely longer lasting because they will remain as long as the edited channels are expressed. We propose to use SDRE to edit NaV1.7 K1395R to render the channel permeable to both Na+ and K+. The purpose of the Administrative Core is to develop an administrative structure to support the goals of the project. This includes committees and guidelines for keeping track of scientific milestones, resolving conflicts in intellectual property and other areas, overseeing budgets and finances, and ensuring accurate and timely reporting to the NIH.

慢性疼痛是残疾的主要原因，影响了全球约三分之一的成年人，患病率很高 比心脏病，癌症和糖尿病大。滥用和滥用阿片类药物已导致 全国成瘾和过量危机。因此，迫切需要替代性，非添加性镇痛药。 非选择性电压门控钠通道（NAV）阻滞剂是现有的非添加性FDA批准 有时可以为患者提供症状的药物。但是，它们的效用受到CNS的限制， 心脏副作用。人类疼痛障碍和疼痛动物模型的遗传和功能研究已有 经过验证的NAV1.7，一种电压门控的NA通道，优先用外周神经元表达为 有吸引力的治疗靶标。但是，同工型选择的NAV阻滞剂很难生成 已经从身体中迅速清除了生成，从而限制了它们的有效性。替代方法是 需要。我们提出了一种通过编辑编码的信息来治疗慢性疼痛的新颖，非依恋的方法 NAV1.7为了改变其电生理特性。通过将单个赖氨酸密码子更改为精氨酸 离子选择性过滤器，该通道将从Na+选择性转到Na+和K+选择性，有效地创建 一个反流的分流，会降低兴奋性。 位置定向的RNA编辑（SDRE）是指在RNA内生成编程编辑的新型机制。它 依赖于ADAR（作用于RNA上的腺苷脱氨酶）酶，该酶是内源表达的 人类细胞，包括感觉神经元。 SDRE系统由导向RNA（GRNA）指导，精确转换 选定的腺苷对肌苷，这是一种转化的鸟嘌呤模仿，可以重新构建特定的氨基酸。为了 用作镇痛作用，编辑mRNA比DNA更可取 效果，包括恶性转化和ADAR是内源性的，而DNA操纵的酶 （例如，CAS蛋白）不是，因此SDRE不会像免疫原性一样。与小分子通道相比 阻滞剂，SDRE可以更具体，因为它依赖于GRNA的Watson-Crick碱基对靶向的基础。 它的效果可能会持续更长，因为只要表达编辑的渠道，它们就会保持持久。 我们建议使用SDRE编辑NAV1.7 K1395R，以使通道可渗透到Na+和K+。这 行政核心的目的是开发行政结构以支持项目的目标。 这包括跟踪科学里程碑的委员会和指南，解决冲突 知识产权和其他领域，监督预算和财务，并确保准确，及时 向NIH报告。