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Principal Investigator: Susan D. Michaelis
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2024
Award: $591,558
Funding agency: National Institute on Aging
PROJECT SUMMARY
This project aims to define the role of farnesylated prelamin A in premature and physiological aging.
Genetic mutations leading to defective processing of prelamin A, the precursor for the nuclear scaffold protein
lamin A, result in persistence of its farnesyl modification and cause premature aging disorders. The best known
of these is Hutchinson-Gilford progeria syndrome (HGPS), in which a truncated farnesylated prelamin A variant
called “progerin” is expressed. Mandibuloacral dysplasia-type B (MAD-B) is a related disease, where
unprocessed farnesylated prelamin A itself accumulates in cells. Some evidence suggests that prelamin A also
accumulates during physiological aging. However, the mechanistic role of farnesylated prelamin A in
premature aging disorders remains unclear, and its association with physiological aging has not been
rigorously tested. We hypothesize that prelamin A is a driver of osteoporosis and cardiovascular
disease that occurs in premature and possibly physiological aging. To specifically examine the
consequences of prelamin A accumulation, we generated a novel mouse strain (LmnaL648R/L648R) with a
mutation that abolishes its processing by the zinc metalloprotease ZMPSTE24. These mice express solely
prelamin A (and no mature lamin A), exhibit profound bone loss, but have a significantly longer lifespan than
other progeria models and are thus ideal to study the effects of prelamin A during aging. In Aim 1, we will
determine how prelamin A affects the number, function, development, transcriptomes and signaling of bone
cells, and compare these to what occurs in physiological aging. We will also assess whether these mice
develop vascular disease as they age or develop accelerated atherosclerosis when combined with genetic
(Ldlr-/-) and high-fat diet interventions that sensitize mice to atherosclerosis. In Aim 2, we will determine how
prelamin A affects cultured cells and define the mechanism(s) by which it promotes cellular alterations related
to aging. We will carry out chronological transcriptomic analyses in cultured cells to define the earliest events
promoted by prelamin A to distinguish causal changes from chronic responses. We will also test the hypothesis
that prelamin A induces nuclear envelope rupture that could stimulate a cytosolic DNA sensor and lead to a
transcriptional program of inflammation. We will relate the mechanistic insights obtained from these in vitro
experiments to affected cells in the LmnaL648R/L648R mice. In Aim 3, we will determine if prelamin A actually
accumulates during physiological aging by examining bone and vascular tissue of young and old mice. We will
also probe human tissue arrays and a panel of fibroblasts from young and aged individuals for prelamin A.
Elucidating the cellular mechanisms and consequences of prelamin A accumulation could change clinical
paradigms for the treatment of prelamin A-based premature aging disorders. More broadly, the results of this
project could rigorously implicate prelamin A in physiological aging, identifying it as a potential therapeutic
target for age-associated osteoporosis, cardiovascular disease, and possibly other ailments.
Terms: <Acceleration><Affect><Age><Age related pathologies><Aging><Animal Model><Animal Models and Related Studies><Antibodies><Arterial Fatty Streak><Arterial Fatty Streaks><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Biological><Blood Vessels><Body Tissues><Bone Development><Bone Resorption><Bone Tissue><C-terminal><Cardiovascular Diseases><Cell Aging><Cell Body><Cell Communication and Signaling><Cell Senescence><Cell Signaling><Cells><Cellular Aging><Cellular Senescence><Chronic><Chronology><Clinical><Cultured Cells><DNA><DNA Alteration><DNA Sequence Alteration><DNA mutation><Data><Defect><Deoxyribonucleic Acid><Deposit><Deposition><Development><Dietary Intervention><Disease><Disorder><Dysplasia><Event><Exhibits><Failure to Thrive><Fibroblasts><Fracture><Gene Transcription><Generalized Growth><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genetic mutation><Grant><Growth><High Fat Diet><Human><Hutchinson-Gilford Disease><Hutchinson-Gilford Syndrome><In Vitro><Inflammation><Inflammatory Response><Intervention><Intervention Strategies><Intracellular Communication and Signaling><LDL Receptors><Lamin A><Lamin Type A><Leiomyocyte><Length><Life><Lipids><Lipoprotein LDL Receptors><Low Density Lipoprotein Receptor><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Metallopeptidases><Metalloproteases><Metalloproteinases><Mice><Mice Mammals><Modeling><Modern Man><Modification><Molecular><Mouse Strains><Murine><Mus><Mutation><Nuclear Envelope><Nuclear Matrix Proteins><Nuclear Matrix-Associated Proteins><Nuclear Membrane><Nuclear Scaffold Protein><Nutrition Interventions><Nutritional Interventions><Older Population><Organism><Osteoblasts><Osteoclastic Bone Loss><Osteoclasts><Osteoporosis><Patients><Persons><Phenotype><Physiologic><Physiological><Point Mutation><Premature Aging><Premature Senility Syndrome><Premature aging syndrome><Progeria><Protein Secretion><Proteins><RNA Expression><Replicative Senescence><Reporting><Role><Rupture><Sequence Alteration><Signal Transduction><Signal Transduction Systems><Signaling><Site><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Stimulator of Interferon Genes><Surface Proteins><Syndrome><Testing><Tissue Arrays><Tissue Chip><Tissue Growth><Tissue Microarray><Tissues><Transcription><Variant><Variation><Vascular Diseases><Vascular Disorder><Vascular Smooth Muscle><Viral><Zinc><Zn element><age associated><age associated pathologies><age correlated><age dependent><age linked><age related><age specific><aged group><aged groups><aged individual><aged individuals><aged mice><aged mouse><aged people><aged person><aged persons><aged population><aged populations><ages><aging associated disease><aging population><aging process><aging related disease><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><biologic><biological signal transduction><blood vessel disorder><bone><bone cell><bone fracture><bone loss><cGAMP STING><cGAMP-STING><cGAMP/STING><cGAS/STING><cardiovascular disorder><cyclic GMP-AMP synthase/STING><developmental><diet intervention><disease of aging><disease phenotype><disorder of aging><dyscrasia><elderly mice><experiment><experimental research><experimental study><experiments><farnesylation><genome mutation><genomic alteration><global gene expression><global transcription profile><human subject><human tissue><in vivo><insight><interventional strategy><lamin A precursor><life span><lifespan><living system><model of animal><mouse model><murine model><natural aging><normal aging><normative aging><novel><old mice><older groups><older individuals><older person><ontogeny><population aging><prelamin A><premature><prematurity><programs><response><senescence><senescent><sensor><social role><therapeutic target><transcriptome><transcriptomics><vascular><vascular dysfunction><vasculopathy><vulnerable plaque>