Combining new molecular and informatic strategies to find hidden ways to treat brain disease

结合新的分子和信息学策略来寻找治疗脑部疾病的隐藏方法

• 批准号: 10307079
• 负责人: ROBERT B DARNELL
• 金额: $ 112.76万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307079
• 关键词: Address; Affect; Astrocytes; Basic Science; Big Data; Biological Models; Brain; Brain Diseases; Cells; Computational Science; DNA; Data Analyses; Defect; Disease; Etiology; Genetic; Goals; Health; Human; Individual; Informatics; Knowledge; Mediating; Methods; Microglia; Modernization; Molecular; Molecular Biology; Neurologist; Neurons; Neurosciences; Patients; Plant Roots; Protein Isoforms; Proteins; RNA; Regulation; Science; Technology; cell type; druggable target; nervous system disorder; new technology; receptor; stoichiometry; success; targeted treatment; therapeutic target

The key challenge addressed in this proposal is to develop a means to harness the power of molecular biology to define therapeutic targets for brain disease. This treatment-oriented approach combines the urgency of a practicing neurologist with the knowledge and technology modern science brings to neuroscience. From the basic science perspective, understanding the fundamental root mechanism of disease is an uncompromising goal. From the neurologist's perspective, the perfect cannot be the enemy of the good, leading to five basic points: · Success to date in the treatment of brain disease offers a key lesson in focus. Treatments target accessible molecules, and this will dictate how we focus big data analysis. · Human neurologic disease is complicated. The best model system for understanding neurologic disorders is the human; studies of human brain material must be integral to developing new treatments. · Regardless of the cause of brain disease—and current neuroscience is appropriately focused on tracing “genetic” (DNA) etiologies—the manifestations of such defects are mediated by the stoichiometry, distribution and variability of cell-specific RNA regulation and its consequent effects on proteins within affected cells. · Different cell types contribute to different brain disorders, but the difference between individual cells of any one type is unknown. The differences between them are manifest at the level of RNA, not DNA. · The quantity, quality (isoforms) and distribution of targets (e.g., receptors) are enormous. The unique spectrum of diversity of an individual cell type—neurons, astrocytes or microglial cells—is unknown, more so when comparing diseased and normal brain. Using a variety of new strategies, we will study RNA regulation in individual cell types. · Bridging these points together requires new methods and computational approaches. · The net result of contrasting RNA regulation in individual human cell types in health and disease will uncover otherwise hidden cell type-specific targets for therapeutics.

该提案解决的关键挑战是开发一种方法，利用分子生物学的力量来定义脑部疾病的治疗靶点。这种以治疗为导向的方法将执业神经科医生的紧迫性与现代科学为神经科学带来的知识和技术结合起来。从基础科学的角度来看，了解疾病的根本根源机制是一个坚定的目标。从神经科医生的角度来看，完美不能成为优秀的敌人，从而得出五个基本点： · 迄今为止在治疗脑部疾病方面取得的成功提供了聚焦的关键教训。治疗以可接近的分子为目标，这将决定我们如何关注大数据分析。 · 人类神经系统疾病很复杂。理解神经系统疾病的最佳模型系统是人类；对人脑物质的研究必须成为开发新疗法的一部分。 · 无论脑部疾病的原因是什么——当前的神经科学适当地专注于追踪“遗传”（DNA）病因——此类缺陷的表现是由细胞特异性 RNA 调节的化学计量、分布和变异性及其对受影响细胞内蛋白质的影响所介导的。 · 不同的细胞类型会导致不同的脑部疾病，但任何一种类型的单个细胞之间的差异尚不清楚。它们之间的差异体现在RNA水平，而不是DNA水平。 · 靶点（例如受体）的数量、质量（异构体）和分布是巨大的。 单个细胞类型（神经元、星形胶质细胞或小胶质细胞）的独特多样性谱是未知的，在比较患病大脑和正常大脑时更是如此。我们将使用各种新策略来研究单个细胞类型中的 RNA 调控。 · 将这些点连接在一起需要新的方法和计算方法。 · 对比健康和疾病中个体人类细胞类型的 RNA 调节的最终结果将揭示隐藏的细胞类型特异性治疗靶点。