Transformative research on somatic gene recombination in the normal and Alzheimer's disease-related dementia brain

项目摘要/摘要 了解人脑及其疾病是一个巨大的挑战，但也是一个机会 改善人类健康。正常大脑的许多显著特征之一是它能够存储和 在一生的学习和记忆中检索信息。阿尔茨海默病(AD)及相关痴呆 (ADRD)破坏这些认知功能，并造成巨大的个人、家庭和社会代价， 尽管有数十种科学理论，但令人不安的是缺乏治疗疾病的方法，数十亿美元 耗资巨大，数十年的研究，以及数百项失败的临床试验。这项变革性的建议将符合 通过研究大脑中一种新发现的分子机制：体细胞基因来应对这些挑战 重组(SGR)。SGR可能通过将神经活动-两者联系起来-改变每个神经元中的单个基因组 正常和异常的DNA基因序列存在于有丝分裂后神经元的基因组中。 我们假设，通过RNA序列的反向插入，形成基因组cDNA(GencDNA)。我们 仅一个基因--AD基因APP--就发现了数千种基因变异，这为我们提供了新的解释 对疾病进展和迄今为止AD治疗的失败负责。这项提案将探讨 SGR作用于ADRDS中的其他已知或未知疾病基因座，并检验SGR失调的假设 代表AD和ADRDS共有的共同致病机制。 一个由世界级ADRD授权的经过验证的调查团队将从事三个领域的研究， 神经科学和生物信息学专家。首先，我们将通过以下方式定义人脑中SGR的机制 识别相关基因并对其功能进行生化表征。第二，我们将使用有针对性的和 无偏方法识别ADRDS中接受SGR的新基因并表征神经解剖学特征 与疾病的典型特征有关的表达。第三，我们将探索可能使用的目标 作为细胞培养和人体体液样本中的生物标志物和治疗学标记。重要的是，这些研究将 通过研究FDA批准的逆转录酶来研究AD和ADRDS的潜在近期治疗方法 抑制剂。这些拟议的研究是第一次检查ADRDS中的SGR，并代表了一条新的研究路线。 这项建议的范围提出了一个真正的变革性研究大脑及其疾病，以及巨大的 认识和治疗ADRDS的挑战。

Project Summary/Abstract Understanding the human brain and its diseases represents an enormous challenge but also an opportunity for improving human health. One of the many remarkable attributes of the normal brain is its ability to store and retrieve information for a lifetime of learning and memories. Alzheimer’s disease (AD) and related dementias (ADRDs) disrupt these cognitive functions and have enormous personal, familial, and societal costs, compounded by a disturbing absence of disease-modifying therapies despite scores of scientific theories, billions of dollars, decades of research, and hundreds of failed clinical trials. This transformative proposal will meet these challenges through studies on a newly identified molecular mechanism within the brain: somatic gene recombination (SGR). SGR may alter individual genomes within each neuron by linking neural activity – both normal and abnormal – to functional DNA gene sequences present within the genomes of post-mitotic neurons. We hypothesize that through retro-insertion of RNA sequences, genomic cDNAs (gencDNAs) are formed. We identified thousands of gene variants for just a single gene – the AD gene, APP – which offers new explanations for disease progression and the failure of AD therapeutics thus far. This proposal will explore the links between SGR acting on other known or unknown disease loci in ADRDs and test the hypothesis that SGR dysregulation represents a common pathogenic mechanism shared by AD and ADRDs. Three areas of study will be pursued by a team of proven investigators empowered by world class ADRD, neuroscience, and bioinformatics experts. First, we will define the machinery of SGR in the human brain by identifying the involved genes and biochemically characterizing their function. Second, we will use targeted and unbiased approaches to identify new genes undergoing SGR in ADRDs and characterize neuroanatomical expression in relation to the classical hallmarks of the disease. Third, we will explore possible targets to be used as biomarkers and for therapeutics in cell culture and human fluid samples. Importantly, these studies will examine a potential near-term therapy for AD and ADRDs by studying FDA-approved reverse transcriptase inhibitors. These proposed studies are the first to examine SGR in ADRDs and represent a new line of research. The scope of this proposal presents a truly transformational study of the brain, its diseases, and the enormous challenge of understanding and treating ADRDs.