A5044369964- Phagocytosis and Immune Regulation
- Atherosclerosis and Cardiovascular Diseases
- Cell death mechanisms and regulation
- Biomarkers in Disease Mechanisms
- MicroRNA in disease regulation
- Immune cells in cancer
- Cancer Immunotherapy and Biomarkers
- PARP inhibition in cancer therapy
- Adipokines, Inflammation, and Metabolic Diseases
- interferon and immune responses
- CRISPR and Genetic Engineering
- Brain Metastases and Treatment
- Nutrition, Genetics, and Disease
- Lung Cancer Treatments and Mutations
- DNA Repair Mechanisms
- Lipoproteins and Cardiovascular Health
- Virus-based gene therapy research
- Immunotherapy and Immune Responses
- Circular RNAs in diseases
- Systemic Lupus Erythematosus Research
- Hippo pathway signaling and YAP/TAZ
- Adipose Tissue and Metabolism
- Cancer Research and Treatments
- RNA Interference and Gene Delivery
- Immune Cell Function and Interaction
University of Ottawa
2018-2024
Yale University
2020-2021
Ottawa Heart Institute
2021
Dalhousie University
2020
Background: Chronic activation of the innate immune system drives inflammation and contributes directly to atherosclerosis. We previously showed that macrophages in atherogenic plaque undergo RIPK3 (receptor-interacting serine/threonine-protein kinase 3)-MLKL (mixed lineage domain-like protein)–dependent programmed necroptosis response sterile ligands such as oxidized low-density lipoprotein damage-associated molecular patterns is active advanced atherosclerotic plaques. Upstream RIPK3-MLKL...
The prevention and treatment of cardiovascular diseases (CVD) has largely focused on lowering circulating LDL cholesterol, yet a significant burden atherosclerotic disease remains even when is low. Recently, microRNAs (miRNAs) have emerged as exciting therapeutic targets for disease. miRNAs are small noncoding RNAs that post-transcriptionally regulate gene expression by degradation or translational inhibition target mRNAs. A number been found to modulate all stages atherosclerosis,...
A significant burden of atherosclerotic disease is driven by inflammation. Recently, microRNAs (miRNAs) have emerged as important factors driving and protecting from atherosclerosis. miR-223 regulates cholesterol metabolism inflammation via targeting both biosynthesis pathway NFkB signaling pathways; however, its role in atherosclerosis has not been investigated. We hypothesize that globally core inflammatory pathways macrophages response to atherogenic stimuli thus limiting the progression...
During the advancement of atherosclerosis, plaque cellularity is governed by influx monocyte-derived macrophages and their turnover via apoptotic nonapoptotic forms cell death. Previous reports have demonstrated that programmed necrosis, or necroptosis, contribute to necrotic core formation. Knockdown inhibition necrosome components RIPK1 (receptor-interacting protein kinase 1) RIPK3 3) slow atherogenesis, activation terminal step MLKL (mixed lineage domain-like protein), has been in...
Despite unique genetic alterations within brain metastases (BrMs) and an immunologically distinct surrounding microenvironment, the composition functional properties of tumor-infiltrating lymphocytes BrM remain largely unexplored. In particular, expression coinhibitory receptors, such as programmed cell death 1 (PD-1), T immunoglobulin mucin receptor 3 (TIM-3), lymphocyte activation gene (LAG-3), BrMs is unknown. Using multiplexed quantitative immunofluorescence (QIF), this study evaluates...
Abstract Introduction: Epithelial ovarian cancers are highly aggressive and often diagnosed at late stages. To date, a limited number of these patients benefit from immunotherapies, recurrent cancer remains an area unmet medical need. Novel immunotherapies that generate drive activated T cells into tumors, such as DPX-Survivac, represent promising approach. better understand the underlying mechanisms action this novel immunotherapy how it may correlate with clinical outcomes, we used...
Background: Atherosclerosis occurs as lipid and immune cell rich plaques deposit within the arterial wall of heart. These cells are produced from hematopoietic stem progenitor (HSPCs) in bone marrow (BM) spleen, a process known hematopoiesis that is dictated by their microenvironment, including endothelial (ECs). Objective: While others have shown adverse remodeling BM ECs during atherogenesis, whether splenic show similar dysfunction leading to exacerbated has not been described. Methods:...
Introduction Chronic activation of the innate immune system drives inflammation and contributes directly to obesity, insulin resistance atherosclerosis. Previously we showed that necroptosis, a pro‐inflammatory form programmed cell death, is activated in vessel wall atherosclerosis via RIP3 MLKL. We sought determine upstream genetic regulators necroptosis metabolic disease, hypothesized gene expression RIP1, key regulatory kinase NFkB activation, apoptosis macrophage cardiometabolic...
During atherosclerosis, macrophages within the aorta undergo necroptosis, a mode of pro-inflammatory cell death that is triggered by phosphorylation RIPK1 & RIPK3 and leads to activation mixed lineage kinase domain-like protein (MLKL) lysis. Our previous work demonstrated while inhibition MLKL decreased necroptosis necrotic core in plaque, unlike this did not lead overall decrease plaque area, suggesting may fact participate other processes drive atherosclerotic development. Because...
The mixed lineage kinase domain-like protein (MLKL) is well-known for its role in the execution of necroptotic cell death. We showed that antisense oligonucleotide knockdown MLKL ( Mlkl KD) Apoe -knockout mice reduces plaque necrotic core, as predicted, but not total area. Additionally, KD expanded splenic hematopoietic stem and progenitor cells (HSPCs) mature myeloid known to drive atherogenesis. Thus, we hypothesized limits hematopoiesis thereby immune contributions growing atheroma. To...
Abstract Poly-ADP-ribose polymerase (PARP) inhibitors are active against cells and tumors with defects in homology-directed repair as a result of synthetic lethality. PARP have been suggested to act by either catalytic inhibition or localization chromatin. In this study, we treat human HCC1937 BRCA1 mutant isogenic -complemented for three weeks veliparib, inhibitor. We show that long-term treatment veliparib results chromatin-bound PARP1 the cells, correlates significant upregulation...
The mixed lineage kinase domain-like protein (MLKL) was first discovered in 2012 as the executioner of necroptosis. In line with this, we showed that MLKL knockdown ( Mlkl KD) by administration antisense oligonucleotides to atherosclerotic-prone Apoe -knockout -/-) mice did indeed decrease necroptosis and necrotic core atherosclerotic plaque. However, there were no changes overall plaque area, suggesting additional roles during atherosclerosis. During atherogenesis, spleen allows for...