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

正常和阿尔茨海默病相关痴呆大脑体细胞基因重组的转化研究

• 批准号: 10400139
• 负责人: JEROLD CHUN
• 金额: $ 92.45万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-11 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10400139
• 关键词: Abbreviations; Affect; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease related dementia; Alzheimer' s disease therapeutic; Alzheimer' s disease therapy; Amyloid beta-Protein Precursor; Amyotrophic Lateral Sclerosis; Area; Biochemical; Bioinformatics; Biological; Biological Markers; Biological Sciences; Biology; Brain; Brain Diseases; Cell Culture Techniques; Cells; Clinical Trials; Cognition; Complementary DNA; Consensus; Copy Number Polymorphism; Custom; DNA; DNA Sequence Alteration; Dementia; Disease; Disease Progression; Endogenous Retroviruses; Enzymatic Biochemistry; Enzymes; Epidemiology; Exposure to; FDA approved; Failure; Fluorescent in Situ Hybridization; Frontotemporal Lobar Degenerations; Genes; Genetic Recombination; Genome; Genomics; Gifts; HIV; Health; Human; Huntington Disease; Immune system; Incidence; Individual; Information Retrieval; Information Storage; Introns; Learning; Lewy Body Dementia; Link; Liquid substance; Medicine; Memory; Mitotic; Molecular; Mosaicism; Nature; Neurobiology; Neurons; Neurosciences; Nucleotides; Parkinson' s Dementia; Pathogenesis; Pathogenicity; Pathologic; Patients; Peptide Nucleic Acids; Ploidies; Prevalence; RAG1 gene; RNA; RNA Sequences; RNA-Directed DNA Polymerase; Research; Research Personnel; Retrieval; Reverse Transcriptase Inhibitors; Sampling; Science; Signal Transduction; Testing; Therapeutic; Therapeutic Uses; Time; V(D)J Recombination; Variant; Work; aged; antiretroviral therapy; base; brain cell; cancer therapy; chimeric antigen receptor T cells; cognitive function; empowered; genetic variant; genome sciences; improved; inhibitor; innovation; insight; new therapeutic target; next generation sequencing; novel marker; novel strategies; programmed cell death protein 1; recombinational repair; relating to nervous system; single molecule; societal costs; theories

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.

项目总结/摘要 了解人类大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属性之一是它存储和储存信息的能力。 为终生的学习和记忆检索信息。阿尔茨海默病（AD）和相关痴呆 （ADRD）扰乱这些认知功能，并造成巨大的个人、家庭和社会成本， 尽管有许多科学理论，但令人不安的是， 数十年的研究，数百次失败的临床试验。这一变革性提案将满足 通过对大脑中一种新发现的分子机制的研究， 重组（SGR）。SGR可能通过连接神经活动来改变每个神经元内的个体基因组， 有丝分裂后神经元基因组中存在的正常和异常至功能性DNA基因序列。 我们假设通过RNA序列的反向插入，形成基因组cDNA（gencDNAs）。我们 仅仅一个基因--AD基因，APP --就发现了数千种基因变异，这提供了新的解释 疾病进展和迄今为止AD治疗的失败。本提案将探讨以下方面之间的联系： SGR作用于ADRD中其他已知或未知的疾病位点，并检验SGR失调 代表AD和ADRD共有的共同致病机制。 三个研究领域将由世界级ADRD授权的经过验证的研究人员团队进行， 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： 鉴定相关基因并以生化方式表征其功能。第二，我们将有针对性地， 无偏倚的方法来识别ADRD中经历SGR的新基因， 与疾病的经典标志相关的表达。第三，我们将探讨可能使用的目标 作为生物标志物和用于细胞培养物和人类流体样品中的治疗。重要的是，这些研究 通过研究FDA批准的逆转录酶，研究AD和ADRD的潜在近期治疗方法 抑制剂的这些拟议的研究是第一次检查ADRD中的SGR，代表了一条新的研究路线。 这项提案的范围提出了一个真正的大脑，它的疾病，以及巨大的变革研究。 对ADRD的理解和治疗的挑战。