Document text
Principal Investigator: Venkateswaran Subramanian
Organization: UNIVERSITY OF MISSOURI-COLUMBIA
Fiscal Year: 2024
Award: $494,578
Funding agency: National Heart Lung and Blood Institute
Abstract
Abdominal aortic aneurysm (AAA) is a permanent dilation of the abdominal aorta with a high mortality
greater than 80% after rupture. Aortic vascular smooth muscle cells (SMCs) are pivotal in maintaining aortic
structural integrity and function, and SMC-rich aortic medial stability is highly disrupted in AAA. Currently,
besides surgical interventions, no alternative therapeutics are available to blunt AAA progression and rupture.
Consequently, there is a dire need to identify novel strategies for development of effective, non-surgical
therapeutics. MicroRNA-146a (miR-146a), a well-known regulator of inflammation and auto-immunity, is highly
expressed in aneurysmal tissue of AAA patients. However, the role of miR-146a in SMC homeostasis and
AAA remains to be explored. In preliminary studies, by in-situ hybridization, we observed that miR-146a is
upregulated in SMC-rich aortic media of human and mouse AAAs; miR-146a deficiency significantly promoted
Angiotensin II (AngII) -induced AAA formation in normolipidemic mice co-administered with Lysyl oxidase inhibitor,
β-aminopropionitrile (BAPN); and mimetics-mediated miR-146a overexpression abolished AngII-induced AAAs in
both hypercholesterolemic LDLr-/- mice and normolipidemic mice co-infused with BAPN. To elucidate underlying
mechanisms, by RNA sequencing, we identified novel targets from miR-146a deficiency experiments: TFIID-31,
a TATA binding protein associated factor involved in transcriptional activation and repression, is significantly
upregulated; whereas Beclin-1, a gene indispensable for autophagy induction and USP9X, a deubiquitinase
critical for Beclin-1 stabilization, are significantly downregulated. Autophagy, a self-regulatory process by
which cells digest, and recycle their cytoplasmic materials for energy purposes under stress. Our preliminary
study also showed an increased Beclin-1 in mouse AAAs, as observed in human AAAs and Tat-peptide
mediated Beclin-1 activation suppressed AngII-induced AAA formation in mice. In addition, miR-146a
overexpression significantly suppressed TFIID-31, promoted USP9X and Beclin-1, and ShRNA-mediated
silencing of TFIID-31 increased USP9X in cultured aortic SMCs. Based on these observations, we will test our
central hypothesis that miR-146a activation protects against AAA formation and progression by promoting
Beclin-1-mediated aortic SMC homeostasis. By utilizing our unique mice models generated specifically for
these studies, we propose 3 aims. Aim 1 will test our working sub-hypothesis that miR-146a promotes Beclin-1
stability in aortic SMCs via a TFIID-31-USP9X –dependent manner. Aim 2 will test our working sub-hypothesis
that miR-146a activation protects against AAA through activation of SMC-Beclin-1-derived autophagy. Aim 3
will determine the effect of miR-146a / Beclin-1 activation on progression of established AAAs. In summary, we
will delineate the protective role of Beclin-1 in AAA and establish miR-146a activation as a novel therapeutic
strategy against AAA by targeting SMC-Beclin-1. This mechanistic research will set solid preclinical evidence
that targeting miR-146a represents a novel therapeutic strategy for treatment and prevention of AAA.
Terms: <3' Untranslated Regions><3'UTR><Abdominal Aortic Aneurysm><AngII><Angiotensin II><Aorta><Autoimmune><Autoimmune Status><Autoimmunity><Autophagocytosis><Autoregulation><BA2R><Binding><Binding Sites><Blood Plasma><Blood leukocyte><Blood monocyte><Body Tissues><Bone Marrow Grafting><Bone Marrow Transplant><Bone Marrow Transplantation><CCG1><Cardiovascular Diseases><Cell Body><Cell Cycle Gene 1><Cell Survival><Cell Viability><Cells><Clinical><Collagen Lysyl Oxidase><Combining Site><Cytoplasm><Death Rate><Deubiquitination><Development><Disease><Disorder><EC 1.4.3.13><Eligibility><Eligibility Determination><Event><Functional RNA><Gene Down-Regulation><Genes><Goals><Homeostasis><Human><Hypercholesteremia><Immunoblotting><In Situ Hybridization><Inflammation><Inflammatory><Infusion><Infusion procedures><Knowledge><LDL Receptors><Leiomyocyte><Leukocytes><Leukocytes Reticuloendothelial System><Lipoprotein LDL Receptors><Low Density Lipoprotein Receptor><Lysyl Oxidase><Marrow Transplantation><Marrow leukocyte><Marrow monocyte><Medial><Mediating><Medical><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modeling><Modern Man><Molecular Interaction><Murine><Mus><Non-Coding><Non-Coding RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Operative Procedures><Operative Surgical Procedures><Outcome><Patients><Peptides><Physiological Homeostasis><Plasma><Plasma Serum><Prevalence><Prevention><Process><Protein-Lysine 6-Oxidase><Proteins><Protocol Screening><RNA Seq><RNA sequencing><RNAseq><Reactive Site><Recycling><Repression><Research><Reticuloendothelial System, Serum, Plasma><Role><Rupture><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Solid><Stress><Surgical><Surgical Interventions><Surgical Procedure><TAF1><TAF1 RNA Polymerase II TATA Box Binding Protein-Associated Factor 250-kD><TAF1 gene><TAF2A><TAFII250><TATA Box Binding Protein-Associated Factor><TATA Box Binding Protein-Like Proteins><TATA Box-Binding Protein-Associated Factor 2A><TATA-Associated Factors><TATA-Binding Protein Associated Factors><TATA-Binding Protein-Related Factors><TBP-Associated Factor Gene><TBP-Associated Factor RNA Polymerase II 250-kD><TBP-Associated Factors><TBP-Like Protein><TBP-Like TLP><TBP-Related Factor><TFIID><Testing><Therapeutic><Tissues><Transcription Activation><Transcription Repression><Transcriptional Activation><Transcriptional Repression><Untranslated RNA><Vascular Smooth Muscle><Western Blotting><Western Immunoblotting><White Blood Cells><White Cell><abdominal aorta><autophagy><beta Aminopropionitrile><cardiovascular disorder><de-ubiquitinase><de-ubiquitinating enzyme><developmental><experiment><experimental research><experimental study><experiments><gene repression><high blood cholesterol><hypercholesterolemia><in silico><in situ Hybridization Genetics><in situ Hybridization Staining Method><infusions><inhibitor><insight><miRNA><miRNAs><mimetics><monocyte><mortality><mortality rate><mortality ratio><mouse model><murine model><new approaches><new drug target><new druggable target><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><noncoding><novel><novel approaches><novel drug target><novel druggable target><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapy approach><novel therapy target><overexpress><overexpression><peripheral blood><pharmacologic><posttranscriptional><pre-clinical><preclinical><prevent><preventing><protein blotting><shRNA><short hairpin RNA><small hairpin RNA><social role><surgery><therapeutic agent development><therapeutic development><transcriptome sequencing><transcriptomic sequencing><treatment strategy><ubiquitin isopeptidase><ubiquitin-specific isopeptidase><white blood cell><white blood corpuscle><β-Aminopropionitrile>