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.

慢性疼痛是导致残疾的主要原因，影响全球约三分之一的成年人， 比心脏病、癌症和糖尿病加起来还要严重。滥用和滥用阿片类药物导致了 全国性的吸毒过量危机因此，迫切需要替代的非成瘾性镇痛剂。 非选择性电压门控钠通道（Nav）阻滞剂是FDA批准的现有非成瘾性药物之一。 有时可以缓解患者症状的药物。然而，它们的实用性受到CNS的限制， 心脏副作用对人类疼痛障碍和疼痛动物模型的遗传和功能研究， 经验证的NaV1.7是一种优先在外周神经元中表达的电压门控Na通道， 有吸引力的治疗目标。然而，亚型选择性Nav阻断剂难以产生， 产生的毒素迅速从体内清除，限制了它们的有效性。替代方法有 needed.我们提出了一种新的，非成瘾性的方法来治疗慢性疼痛，通过编辑编码的信息， NaV1.7，以改变其电生理特性。通过改变一个单一的赖氨酸密码子精氨酸在 离子选择性过滤器，通道将从Na+选择性变为Na+和K+选择性，有效地产生 一个能抑制兴奋性的逆流分流器 定点RNA编辑（SDRE）是指在RNA内产生程序化编辑的新机制。它 依赖于阿达尔（作用于RNA的腺苷脱氨酶）酶，其在细胞中内源性表达。 人类细胞，包括感觉神经元。在向导RNA（gRNA）的指导下，SDRE系统精确地转化 选择的腺苷转化为肌苷，肌苷是鸟苷的翻译模拟物，可以重新编码特定的氨基酸。为 作为止痛药，编辑mRNA优于DNA，因为它是瞬时的，从而限制了潜在的脱靶 影响，包括恶性转化和ADAR是内源性的，而DNA操作酶 (e.g. Cas蛋白）不是，因此SDRE不会具有免疫原性。与小分子通道相比 阻断剂，SDRE可以更特异，因为它依赖于gRNA的沃森-克里克碱基配对用于靶向， 并且其效果可能持续更长时间，因为只要编辑的频道被表达，它们就将保持。 我们建议使用SDRE来编辑NaV1.7 K1395 R，以使通道对Na+和K+都是可渗透的。的 行政核心的目的是建立一个行政结构，以支持项目的目标。 这包括委员会和指导方针，以跟踪科学里程碑，解决冲突， 知识产权和其他领域，监督预算和财务，并确保准确和及时 向NIH报告。