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

本提案提出的关键挑战是开发一种方法来利用分子生物学的力量来确定脑部疾病的治疗靶点。这种以治疗为导向的方法结合了执业神经科医生的紧迫性和现代科学给神经科学带来的知识和技术。从基础科学的角度来看，了解疾病的根本机制是一个不可妥协的目标。从神经学家的角度来看，完美不可能是好的敌人，这就引出了五个基本要点：·迄今为止，治疗脑部疾病的成功提供了一个关键的教训，那就是专注。治疗的目标是可获得的分子，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；对人类大脑物质的研究必须是开发新疗法不可或缺的一部分。·不管脑病的病因是什么——目前的神经科学正适当地关注于追踪“遗传”（DNA）病因——这些缺陷的表现是由细胞特异性RNA调控的化学计量、分布和变异性及其对受影响细胞内蛋白质的后续影响所介导的。·不同的细胞类型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是未知的。它们之间的差异体现在RNA水平上，而不是DNA水平上。·靶标（如受体）的数量、质量（同种异构体）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，在比较患病和正常大脑时更是如此。使用各种新的策略，我们将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调控的最终结果将揭示治疗中隐藏的细胞类型特异性靶点。

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.