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Principal Investigator: Yanhong Guo
Organization: UNIVERSITY OF MICHIGAN AT ANN ARBOR
Fiscal Year: 2023
Award: $763,935
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY/ABSTRACT
Abdominal aortic aneurysm (AAA) is defined as a permanent, localized dilatation of the abdominal aorta with
the potentially fatal consequence of aortic rupture. The only effective treatment for AAA is open or
endovascular surgical repair when AAA patients with symptomatic or large AAA. The vast majority of AAA are
below the threshold for surgical repair and 50-70% of small AAAs eventually progress to a stage requiring
surgical repair. Currently, there is no effective medical therapy for these patients to reduce aneurysm growth
and reduce the risk of rupture, highlighting an urgent need to develop effective medical treatments to prevent
aneurysm growth and reduce the risk of rupture. Chronic inflammation and vascular smooth muscle (VSMC)
dysfunction have been well documented in AAA pathogenesis in both AAA patients and animal models. Our
study and others have shown that macrophage infiltration and VSMC dysfunction can be noted at a very early
stage of AAA induction. Inhibition of inflammatory activation effectively reduces development and progression
of AAA in animal models. However, several clinical trials have reported no efficacy of several drugs with anti-
inflammatory properties to limit AAA progression, indicating a need of new strategies by targeting AAA lesions
and suppressing inflammatory responses and preserving VSMC function to prevent and treat AAA. We have
been developing nanoparticles (NP) to treat cardiovascular disease since 2014, in which small size NP and/or
encapsulated with active therapeutic agents can be precisely applied to the target sites, such as
atherosclerotic plaques and AAA lesions. Recently, we generated a novel phospholipid NP (PLN), miNano
(Michigan Nanoparticle), which could accumulate in AAA lesions. Our previous studies have demonstrated that
Krüppel-like factor 14 (KLF14) has strong anti-inflammatory effects by directly suppressing the nuclear factor-
κB p65 expression. Recently, we found that KLF14 play an important role in maintaining VSMC function. Our
preliminary studies found that nitro-oleic acid (OA-NO2), a compound currently in Phase 2 clinical trials, could
induce KLF14 expression and shows VSMC protective effects in a KLF14-dependent manner. Administration
of OA-NO2 protects against AAA formation and progression in mouse model. Based on these findings, we
propose the central hypothesis that PLN-mediated delivery OA-NO2, a KLF14 inducer, protects against AAA
pathogenesis by maintaining VSMC function and inhibiting vascular inflammation. Aim 1. Define that OA-NO2-
KLF14 is a protective pathway in AAA pathogenesis. Aim 2. Develop PLN as an efficient AAA drug delivery
system. Aim 3. Determine the ability of PLN-OA-NO2 to reduce AAA dissection and rupture in vivo. This study
will promote the development of novel pharmacological therapies for AAA by PLN-mediated targeted drug
delivery for highly efficient, more feasible and less side effects.
Terms: <21+ years old><9-Octadecenoic Acid><Abdominal Aortic Aneurysm><Acceleration><Adult><Adult Human><Aneurysm><AngII><Angiotensin II><Animal Model><Animal Models and Related Studies><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatories><Antiinflammatory Agents><Antiinflammatory Effect><Aorta><Aortic Rupture><Arterial Fatty Streak><Arterial Fatty Streaks><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atheroscleroses><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Bioavailability><Biological Availability><Cardiovascular Diseases><Cause of Death><Cell Body><Cells><Characteristics><Chronic><Chronic Disease><Chronic Illness><Chronic Kidney Failure><Chronic Renal Disease><Chronic Renal Failure><Clinical Trials><Data><Development><Dilatation><Dilatation - action><Disease><Disorder><Dissection><Drug Delivery><Drug Delivery Systems><Drug Kinetics><Drug Targeting><Drug Therapy><Drugs><Dysfunction><Elastases><Encapsulated><Extracellular Matrix Degradation><Fatty Acids><Formulation><Functional disorder><Generalized Growth><Genetic study><Growth><Homolog of Drosophila TOLL><Human><Human Genetics><Image><Infiltration><Inflammation><Inflammatory><Inflammatory Response><Infusion><Infusion procedures><Leiomyocyte><Lesion><Libraries><Lung diseases><Macrophage><Mediating><Medical><Medication><Mice><Mice Mammals><Michigan><Modeling><Modern Man><Morbidity><Morbidity - disease rate><Murine><Mus><Muscle Atrophy><Muscle function><Muscular Atrophy><Mφ><NO2><Names><Nitrogen Dioxide><Nitrogen Peroxide><Nuclear><Oleic Acids><Operative Procedures><Operative Surgical Procedures><Pathogenesis><Pathologic><Pathway interactions><Patients><Pharmaceutic Preparations><Pharmaceutical Preparations><Pharmacokinetics><Pharmacotherapy><Phase 2 Clinical Trials><Phase II Clinical Trials><Phosphatides><Phospholipids><Physiologic Availability><Physiopathology><Play><Property><Protein Cleavage><Proteolysis><Pulmonary Diseases><Pulmonary Disorder><Reporting><Risk Reduction><Role><Rupture><Ruptured Aneurysm><Site><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Stimulus><Surgical><Surgical Interventions><Surgical Procedure><TLR4><TLR4 gene><Therapeutic><Therapeutic Agents><Tissue Growth><Toll Homologue><Toxic effect><Toxicities><Vascular Smooth Muscle><Work><abdominal aorta><adulthood><anti-inflammatory effect><antiinflammatory><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><beta Aminopropionitrile><cardiovascular disorder><chronic disorder><chronic kidney disease><cis-9-Octadecenoic Acid><developmental><disease of the lung><disorder of the lung><drug release kinetics><drug release rate><drug treatment><drug/agent><effective therapy><effective treatment><fat metabolism><imaging><in vivo><infusions><lipid metabolism><lung disorder><model of animal><mortality><mouse model><murine model><muscle breakdown><muscle degradation><muscle deterioration><muscle loss><muscle wasting><name><named><naming><nano particle><nano-sized particle><nanoparticle><nanosized particle><nanotherapeutic><new approaches><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><nitroalkene><novel><novel approaches><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><ontogeny><p65><particle><pathophysiology><pathway><pharmacologic><phase II protocol><preservation><prevent><preventing><protection pathway><protective effect><protective pathway><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><repair><repaired><risk-reducing><scRNA-seq><side effect><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><surgery><therapeutically effective><toll-like receptor 4><vascular inflammation><vulnerable plaque><β-Aminopropionitrile>