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。在正常大脑的许多显着属性中，其存储能力和检索一生的学习和记忆的信息，仍然是生活中的喜悦和神秘感之一。阿尔茨海默氏症疾病（AD）破坏了这些认知功能，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。该变革性建议将通过对新确定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）。 NGR可能会改变内部的个体基因组每个神经元通过将神经元活性（正常和异常）与功能性DNA基因序列联系起来。有丝分裂后神经元的基因组，通过重新插入RNA序列的过程来产生基因组cDNA（GenCDNA）。仅用于单个基因的数千种基因 - AD基因 APP - 到目前为止提供了有关疾病进展和AD疗法徒劳的新解释。三个区域研究将由世界一流的生物信息学授权的一组研究人员进行研究，阿尔茨海默氏病和神经科学专家。首先，我们将定义人脑中NGR的机械通过识别涉及的基因并从生化表征其功能。其次，我们将正式定义通过分析足够数量的零星广告大脑，与主要形式的AD和治疗相关的NGR相关，以及研究与家庭广告和唐氏综合症的关系以识别共享分子病因。这些研究还将通过研究FDA批准来检查AD的潜在近期治疗逆转录酶抑制剂及其对广告端点的影响，该抑制剂将基于科学基于NGR的基础。第三，我们将使用靶向和公正的方法来识别新的NGR基因以及他们与其他脑部疾病的关系，尤其是那些涉及零星脑疾病的人广告。这些研究是第一个检查NGR的研究，代表了一项新的研究线，没有事先的NIH支持，具有不适合标准的NIH机制的范围，朝着对大脑的真正变革性研究，ITS的真正变革性研究疾病和广告的巨大挑战。