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Principal Investigator: Jonathan J Miner
Organization: UNIVERSITY OF PENNSYLVANIA
Fiscal Year: 2024
Award: $795,004
Funding agency: National Institute of Neurological Disorders and Stroke
Project Abstract
The goal of this proposal is to define the mechanisms of retinal vasculopathy with cerebral leukoencephalopathy
(RVCL), an adult-onset vascular dementia associated with brain atrophy, blindness, and premature death,
usually within 5-10 years of disease onset. RVCL is an autosomal dominant disease that is refractory to treatment
with immunosuppression despite the fact that RVCL patients develop autoantibodies. RVCL-causing mutations
in the TREX1 gene cause disease with 100% penetrance. Currently, there is no effective treatment for this
devastating disease, and the mechanisms of disease pathogenesis have not yet been defined.
Dr. Jonathan Miner (PI) directs the RVCL Research Center at the University of Pennsylvania and coordinates
care of RVCL patients from around the United States and the world. Dr. Miner also leads a team of RVCL-
focused clinicians and investigators. Preliminarily the Miner laboratory has generated numerous mouse and
human cellular models of RVCL and discovered novel molecular mechanisms that may be driving
endotheliopathy, cellular senescence, and the resulting vascular dementia. The co-investigator is Dr. Nouri
Neamati, a medicinal chemist and biochemist at the University of Michigan. Dr. Neamati is developing TREX1
inhibitors and protein degraders. This partnership has led to novel animal models, single-cell RNA-seq studies,
and first-in-class inhibitors of TREX1, as well as our discovery that RVCL-causing TREX1 mutations lead to
failure of replicative senescence and dysregulation of endogenous retroelements.
Here, we propose to use cellular and animal models to define the role of TREX1 in regulating DNA damage,
retroelements, and pathology (Aim 1), to use animal models to define functions of TREX1 mutants and a DNA
damage repair pathway in humoral immunity (Aim 2), and to determine the role of TREX1 DNase activity using
an enzyme-dead TREX1 mutant mice and first-in-class TREX1 inhibitors and protein degraders (Aim 3). Our
mechanistic studies will broadly elucidate functions of TREX1 and the role of TREX1-mediated DNA damage in
a mouse model expressing TREX1 mutants known to cause small vessel disease and vascular dementia in
humans. Insights gained from our work may clarify the role of TREX1 and endogenous retroviruses in cellular
senescence, eventually leading to new therapies for this monogenic vascular dementia.
Terms: <21+ years old><3 Prime Repair Exonuclease 1 Gene><ATR-Interacting Protein Gene><ATRIP><ATRIP Gene><Adult><Adult Human><Affect><Age><Aging><Amentia><Animal Model><Animal Models and Related Studies><Arteriosclerotic Dementia><Autoantibodies><Autoimmune Status><Autoimmunity><Automobile Driving><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Blindness><Blood Vessels><Brain Diseases><Brain Disorders><C-terminal><Cause of Death><Cell Aging><Cell Body><Cell Death><Cell Nucleus><Cell Senescence><Cell model><Cells><Cellular Aging><Cellular Senescence><Cellular model><Cerebral small vessel disease><Cerebrum><Cessation of life><Chromatin Structure><Chronic><Cytosol><DKFZp434J0310 Gene><DNA><DNA Damage><DNA Damage Repair><DNA Injury><DNA Nucleases><DNA Repair><DNA Sequence><DNase><DNase III Gene><DRN3 Gene><Death><Dementia><Deoxyribonuclease III, DnaQ/MutD (E. coli)-Like Gene><Deoxyribonucleases><Deoxyribonucleic Acid><Disease><Disorder><ERVs><Encephalon Diseases><Endogenous Retroviruses><Endoplasmic Reticulum><Enzyme Gene><Enzymes><Ergastoplasm><Euchromatin><FLJ12343 Gene><Failure><Family><Frame Shift Mutation><Frameshift Mutation><Genetic Alteration><Genetic Change><Genetic defect><Genome><Genomic DNA><Goals><HERVs><Hereditary><Heterochromatin><Heterozygote><Human><Human Endogenous Retroviruses><Human Genome><Humoral Immunities><IFN><Immune><Immunes><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Individual><Inherited><Interferons><Intracranial CNS Disorders><Intracranial Central Nervous System Disorders><Investigators><Knock-out><Knockout><Laboratories><Lead><Lesion><Leukoencephalopathy><Mammalian Cell><Mediating><Medicine><Mice><Mice Mammals><Michigan><Microvascular Dysfunction><Modeling><Modern Man><Molecular><Murine><Mus><Mutant Strains Mice><Mutation><Nucleus><Onset of illness><Organ><PARP Inhibitor><PARP-1 inhibitor><PARPi><Pathogenesis><Pathology><Pathway interactions><Patients><Pb element><Penetrance><Pennsylvania><Phenotype><Poly(ADP-ribose) Polymerase Inhibitor><Poly(ADP-ribose) polymerase 1 inhibitor><Population><Predisposition><Premature Aging><Premature aging syndrome><Production><Proteins><Reading Frame Shift Mutation><Refractory><Replicative Senescence><Research><Research Personnel><Researchers><Retina><Retroelements><Retroviridae><Retroviruses><Role><Sampling><Serology><Stimulator of Interferon Genes><Susceptibility><TREX1><TREX1 gene><TREX1 protein><Tcr region expressed 1 protein><Testing><Three Prime Repair Exonuclease 1 Gene><Transgenic Mice><United States><Universities><Unscheduled DNA Synthesis><Vascular Dementia><Vascular Diseases><Vascular Disorder><Viral><Virus-Retrovirus><Work><adulthood><age associated><age correlated><age dependent><age linked><age related><age specific><ages><antibody-based immunity><autoimmune antibody><autoreactive antibody><autosome><blood vessel disorder><brain atrophy><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><care coordination><cell type><cerebral><cerebral atrophy><cerebral small vessel disorder><chromatin remodeling><coordinating care><cortical atrophy><cyclic GMP-AMP synthase/STING><disability><disease onset><disorder onset><driving><effective therapy><effective treatment><enzyme activity><gDNA><genome mutation><heavy metal Pb><heavy metal lead><heterozygosity><human disease><human whole genome><immune suppression><immune suppressive activity><immune suppressive function><immunosuppressive activity><immunosuppressive function><immunosuppressive response><inhibitor><innovate><innovation><innovative><insight><mammalian genome><microvascular complications><microvascular disease><model of animal><mouse model><mouse mutant><murine model><mutant><necrocytosis><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutics><novel therapy><pathway><premature><prematurity><prevent><preventing><pro-aging><progeronic><promote aging><response><restraint><scRNA-seq><self reactive antibody><senescence><senescent><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small vessel disease><social role><substantia alba><vascular><vascular contributions to dementia><vascular dysfunction><vasculopathy><viral DNA><virus DNA><vision loss><visual loss><white matter>