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：
10021892
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/10021892
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 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&apos 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/antagonist 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

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.

项目概要/摘要了解人脑及其疾病是一个巨大的挑战，但也是一个机遇改善人类健康正常大脑的众多显着属性之一是其存储和存储的能力。检索有助于终生学习和记忆的信息。（ADRD）会破坏这些认知功能，并造成巨大的个人、家庭和社会成本，令人不安的是，尽管有大量的科学理论，但仍缺乏缓解疾病的疗法，数十亿人这项变革性的提案将花费数十年的研究和数百次失败的临床试验。通过对大脑内新发现的分子机制的研究来应对这些挑战：体细胞基因重组（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。正常和异常——有丝分裂后神经元基因组中存在的功能性 DNA 基因序列。我们认为，通过逆向插入 RNA 序列，可以形成基因组 cDNA (gencDNA)。仅针对一个基因（AD 基因，APP）识别出数千个基因变异，这提供了新的解释该提案将探讨迄今为止疾病进展和 AD 治疗失败之间的联系。 SGR 作用于 ADRD 中其他已知或未知的疾病位点，并检验 SGR 失调的假设代表 AD 和 ADRD 共有的共同致病机制。由世界级 ADRD 授权的经过验证的研究人员团队将开展三个研究领域，首先，我们将通过以下方式定义人脑中的 SGR 机制。其次，我们将使用有针对性的方法来识别相关基因并对其功能进行生化表征。公正的方法来识别 ADRD 中经历 SGR 的新基因并表征神经解剖学特征第三，我们将探索可能使用的目标。重要的是，这些研究将作为细胞培养物和人体液体样本中的生物标志物和治疗方法。通过研究 FDA 批准的逆转录酶来研究 AD 和 ADRD 的潜在近期疗法这些拟议的研究是第一个检查 ADRD 中 SGR 的研究，代表了一个新的研究方向。该提案的范围提出了对大脑、其疾病以及巨大的影响的真正变革性研究。理解和治疗 ADRD 的挑战。