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

基本信息

批准号：
10640064
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
项目类别：
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/10640064
关键词：
Abbreviations Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease related dementia Alzheimer&apos s disease therapeutic Alzheimer&apos 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 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 Molecular Neuroanatomy Neurobiology Neurons Neurosciences Nucleotides Parkinson&apos s Dementia Pathogenesis Pathogenicity Pathologic Patients Peptide Nucleic Acids Ploidies Prevalence RAG1 gene RNA RNA Sequences RNA-Directed DNA Polymerase Rag1 Mouse 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 brain cell cancer therapy chimeric antigen receptor T cells cognitive function empowerment genetic variant genome sciences improved innovation insight mosaic nature neural new therapeutic target next generation sequencing novel marker novel strategies postmitotic programmed cell death protein 1 repaired single molecule societal costs theories

项目摘要

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。正常大脑的众多显着属性之一是其存储和检索一生的学习和记忆的信息。阿尔茨海默氏病（AD）和相关痴呆症（ADRDS）破坏这些认知功能，并具有巨大的个人，家庭和社会成本，由于缺乏疾病修改的疗法的目的地得分，数十亿美元，数十年的研究以及数百个失败的临床试验。这个变革性的建议将满足通过研究大脑内新鉴定的分子机制的研究：体细胞基因重组（SGR）。 SGR可以通过连接神经元活性来改变每个神经元内的个体基因组 - 既可以正常和异常 - 在有丝分裂后神经元基因组中存在的功能性DNA基因序列。我们假设通过重新插入RNA序列，形成了基因组cDNA（GENCDNA）。我们仅为一个基因（广告基因，应用程序）确定了数千种基因变体，该基因提供了新的解释迄今为止，用于疾病进展和AD疗法的失败。该建议将探讨 SGR作用于ADRD中其他已知或未知疾病的地方，并检验了SGR失调的假设代表AD和ADRD共有的常见致病机制。一个研究领域将由一个由世界一流的研究人员进行的研究团队，神经科学和生物信息学专家。首先，我们将通过识别所涉及的基因并在生化中表征其功能。其次，我们将使用针对性的无偏的方法来识别ADRD中经历SGR的新基因并表征神经解剖学与疾病的经典标志有关的表达。第三，我们将探索使用的可能目标作为生物标志物以及细胞培养和人体液体样品的治疗。重要的是，这些研究将通过研究FDA批准的逆转录酶检查AD和ADRD的潜在近期治疗抑制剂。这些拟议的研究是第一个研究ADRD中的SGR并代表新的研究系列的研究。该提案的范围提出了对大脑，疾病和巨大的真正变革性研究理解和治疗ADRD的挑战。