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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.

项目总结/文摘