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Principal Investigator: JEROLD CHUN
Organization: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
Fiscal Year: 2024
Award: $929,705
Funding agency: National Institute on Aging
PROJECT SUMMARY/ABSTRACT
We have identified somatic gene recombination (SGR) in neurons of the human brain, with particular relevance
to sporadic Alzheimer’s disease (SAD) (Nature 563, 639-645 (2018)). This discovery represents a new and
functionally significant aspect of genomic mosaicism (eLife;4:e05116 (2015)) that has genuine therapeutic
potential through newly identified molecular targets. Indeed, we found that SGR, acting on the AD gene for
Amyloid Precursor Protein (APP), produces thousands of distinct forms of APP, some of which are enriched in
or unique to AD. The APP gene variations related to AD that were analyzed thus far include copy number
variations (CNVs) and at least 11 single-nucleotide variations (SNVs) that were previously reported as
pathogenic in familial AD, yet that arose somatically and mosaically in SAD; these variations were absent from
non-diseased neurons. SGR utilizes reverse transcriptase (RT) activity on transcribed RNAs that, combined
with DNA strand-breaks and APP gene transcription, produce double-stranded DNA that is retro-inserted back
into the genome to form “genomic cDNAs” (gencDNAs). These published data contribute to the scientific
foundation on which the current proposal will build, to test the hypothesis that altered SGR, involving brain-
specific reverse transcriptases, functionally contributes to AD and affects multiple genes, providing novel targets
for AD therapies. Postmortem IRB-approved and de-identified brain samples from validated AD donors of both
sexes will be compared to non-diseased controls, while IACUC-approved animal experiments will model SGR
and its AD-relevant endpoints. Three Aims will be pursued over 5 years. Aim 1 will define the molecular
neurobiology of APP gencDNA diversity and identify new SGR genes enhanced in AD brains. Aim 2 will
determine expression and function of SGR genes in AD brain and model systems. Aim 3 will identify genes
responsible for RT SGR activity within normal and AD brains. This proposal will thus open new vistas into AD
via novel SGR mechanisms and will identify new therapeutic targets for the treatment of AD.
Terms: <AD dementia><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affect><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's brain><Alzheimer's disease brain><Alzheimer's disease therapeutic><Alzheimer's disease therapy><Alzheimer's therapeutic><Alzheimer's therapy><Alzheimers Dementia><Amyloid (Aβ) plaques><Amyloid A4 Protein Precursor><Amyloid Plaques><Amyloid Protein Precursor><Amyloid beta-Protein Precursor><Amyloid β-Protein Precursor><Animal Experiments><Animal Model><Animal Models and Related Studies><Autopsy><Back><Biologic Models><Biological Models><Brain><Brain Nervous System><Brain region><Cell model><Cellular model><Complementary DNA><Copy Number Polymorphism><DNA><DNA Molecular Biology><DNA Recombination><DNA strand break><Data><Deoxyribonucleic Acid><Disease><Disorder><Dorsum><Double-Stranded DNA><Down's Syndrome><EC 2.7.7.49><Encephalon><FDA approved><Female><Foundations><Gene Proteins><Gene Transcription><Gene variant><Genes><Genetic Recombination><Genetic Transcription><Genome><Genomics><Glia><Glial Cells><HIV><Human><Human Immunodeficiency Viruses><IACUC><IRB><IRBs><In Situ Hybridization><Institutional Animal Care and Use Committee><Institutional Review Boards><Knowledge><Kolliker's reticulum><LAV-HTLV-III><Langdon Down syndrome><Lymphadenopathy-Associated Virus><Methodology><Model System><Modeling><Modern Man><Molecular><Molecular Biology><Molecular Neurobiology><Molecular Target><Mongolism><Mosaicism><Nature><Nerve Cells><Nerve Unit><Neural Cell><Neuritic Plaques><Neurocyte><Neurofibrillary Tangles><Neuroglia><Neuroglial Cells><Neurons><Non-Polyadenylated RNA><Non-neuronal cell><Nonneuronal cell><Nucleotides><Pathogenicity><Patients><Pattern><Prevalence><Primary Senile Degenerative Dementia><Protein Gene Products><Publishing><RNA><RNA Expression><RNA Gene Products><RNA Transcriptase><RNA-Dependent DNA Polymerase><RNA-Directed DNA Polymerase><Recombination><Reporting><Reverse Transcriptase><Reverse Transcriptase Inhibitors><Revertase><Ribonucleic Acid><Role><Sampling><Senile Plaques><Testing><Therapeutic><Toxic effect><Toxicities><Transcription><Trisomy 21><Validation><Variant><Variation><Virus-HIV><aged><allele variant><allelic variant><amyloid beta plaque><amyloid precursor protein><amyloid-b plaque><animal experiment><aβ plaques><brain tissue><cDNA><cell type><chromosome 21 trisomy syndrome><congenital acromicria syndrome><copy number variant><copy number variation><cored plaque><diffuse plaque><ds-DNA><dsDNA><experimental animal><experimental animals><familial AD><familial Alzheimer><familial Alzheimer disease><genetic variant><genomic variant><hESC><human ES cell><human ESC><human embryonic stem cell><iPS><iPSC><iPSCs><in situ Hybridization Genetics><in situ Hybridization Staining Method><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><integration site><male><model of animal><morbus Down><mosaic><mosaic diseases><mosaic disorders><nanobodies><nanobody><necropsy><nerve cement><neurobiological mechanism><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neuronal><neuropathologic><neuropathological><neuropathology><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><postmortem><primary degenerative dementia><pseudohypertrophic progressive muscular dystrophy><sdAb><senile dementia of the Alzheimer type><sequencing platform><sex><single domain antibodies><social role><tangle><therapeutic target><trisomy 21 syndrome><validations>