Transformative research on the normal and Alzheimer's disease brain through studies of neuronal gene recombination

通过神经元基因重组研究对正常和阿尔茨海默病大脑进行变革性研究

基本信息

批准号：
9983245
负责人：
JEROLD CHUN
金额：
$ 244.99万
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：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2020-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9983245
关键词：
Affect Age Alzheimer&apos s Disease Amyloid Beta A4 Precursor Protein Area Biochemical Bioinformatics Biological Biology Brain Brain Diseases CAR T cell therapy Cells Clinical Trials Clinical assessments Cognition Cognitive Complementary DNA Custom DNA Development Disease Disease Progression Down Syndrome Enzymatic Biochemistry Epidemiology Etiology FDA approved Foundations Frontotemporal Dementia Futility Generations Genes Genetic Recombination Genome Genomics HIV Health Human Human Genetics Immune system Incidence Individual Information Retrieval Information Storage Instruction Lead Learning Lewy Body Dementia Life Link Medicine Memory Mitotic Molecular Mosaicism Neurobiology Neurons Neurosciences Parkinson Disease Pathogenicity Pathologic Patients Prevalence Process RNA Sequences RNA-Directed DNA Polymerase Research Research Personnel Reverse Transcriptase Inhibitors Safety Science Signal Transduction Techniques Therapeutic Treatment Failure United States National Institutes of Health V(D)J Recombination aged antiretroviral therapy base cancer therapy cognitive function empowered epidemiologic data familial Alzheimer disease gene discovery genetic variant genome sciences innovation new therapeutic target next generation sequencing novel therapeutics relating to nervous system 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 bettering human health. Among the many remarkable attributes of the normal brain, its ability to store and retrieve information for a lifetime of learning and memories, remains one of life’s joys and mysteries. Alzheimer’s disease (AD) disrupts these cognitive functions and has 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: neuronal gene recombination (NGR). NGR may alter individual genomes within each neuron by linking neural activity – both normal and abnormal – to functional DNA gene sequences within the genomes of post-mitotic neurons, doing so through a process of retro-insertion of RNA sequences to produce genomic cDNAs (gencDNAs). The resulting thousands of gene variants for just a single gene – the AD gene APP – offers new explanations for disease progression and the futility of AD therapeutics thus far. Three areas of study will be pursued with a team of proven investigators empowered by world class bioinformatics, Alzheimer’s disease, and neuroscience experts. First, we will define the machinery of NGR in the human brain by identifying involved genes and biochemically characterizing their function. Second, we will formally define NGR relevance to major forms of AD and therapeutics by analyses of a sufficient number of sporadic AD brains, as well as examining relationships to familial AD and Down syndrome towards identifying shared molecular etiologies. These studies will also examine a potential near-term therapy for AD by studying FDA-approved reverse transcriptase inhibitors and their impact on AD endpoints, which would be grounded in a scientific foundation based upon NGR. Third, we will use targeted and unbiased approaches to identify new NGR genes and their relationships to other brain diseases, particularly those involved with sporadic brain disorders beyond AD. These studies are the first to examine NGR, representing a new line of research without prior NIH support, with a scope not amenable to standard NIH mechanisms, towards truly transformational studies of the brain, its diseases, and the enormous challenge of AD.

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具有许多显着的属性，其中之一就是其存储和存储的能力。检索信息以供终生学习和记忆，仍然是阿尔茨海默病的一大乐趣和奥秘。疾病（AD）会破坏这些认知功能，并造成巨大的个人、家庭和社会成本，尽管有大量的科学理论，但令人不安的是，疾病缓解疗法的缺乏，使情况变得更加复杂。美元、数十年的研究和数百次失败的临床试验。这项变革性的提案将通过对新发现的分子的研究来应对这些挑战大脑内的机制：神经元基因重组（NGR）可能会改变个体基因组。每个神经元通过将神经活动（正常和异常）与内部的功能 DNA 基因序列联系起来有丝分裂后神经元的基因组，通过逆向插入 RNA 序列的过程来产生基因组 cDNA (gencDNA) 仅针对一个基因（AD 基因）就产生了数千个基因变体。 APP – 为疾病进展和迄今为止 AD 疗法的无效性提供了新的解释三个领域。研究将由一支由世界一流生物信息学授权的经过验证的研究人员团队进行，首先，我们将定义人脑中 NGR 的机制。其次，我们将正式定义相关基因并对其功能进行生化表征。通过分析足够数量的散发性 AD 大脑，NGR 与 AD 的主要形式和治疗方法相关，以及检查与家族性 AD 和唐氏综合症的关系，以确定共有的分子这些研究还将通过研究 FDA 批准的 AD 潜在的近期治疗方法。逆转录酶抑制剂及其对 AD 终点的影响，这将基于科学依据第三，我们将使用有针对性的、公正的方法来识别新的NGR基因。及其与其他脑部疾病的关系，特别是那些与其他脑部疾病有关的散发性脑部疾病 AD. 这些研究是第一个检查 NGR 的研究，代表了没有 NIH 事先支持的新研究领域，其范围不符合标准的 NIH 机制，旨在对大脑进行真正的变革性研究，其疾病，以及 AD 的巨大挑战。