Research
Overview
The Näär lab focuses on understanding metabolic aberrations underlying rare and prevalent diseases to develop novel therapeutic approaches.
How we do it
Explore our Research Areas
Key Areas: microRNAs (miRNAs), antisense oligonucleotides, metabolic syndrome, nonalcoholic fatty liver disease (NAFLD), muscular dystrophy, transcriptional regulatory control, lipogenic mechanistic principles
Sirius Red staining of DMD muscle
H&E staining of fatty liver tissue
Protein N staining of SARS-CoV-2 infected lung tissue
IgG/IgM staining with DAPI of DMD muscle
EM image of WT mouse muscle
In vitro fluorescence in situ hybridization (FISH) of ASO
Featured publication:
Zhu C, Lee JY, Woo JZ, Xu L, et al..Näär AM.
An intranasal ASO therapeutic targeting SARS-CoV-2
Nature Communications 2022. 13:4503.
Antisense based therapeutic targeting of pathogenic RNA viruses
Antisense oligonucleotides (ASOs) hold great promise in therapeutic targeting of pathological RNAs. We have applied our deep expertise with locked nucleic acid (LNA) ASO technologies to target RNA viruses of great societal concern, including Ebola and SARS-CoV-2. When the Covid-19 pandemic began in earnest in the U.S., our lab pivoted to designing and testing LNA ASOs targeting the SARS-CoV-2 viral RNA. We were successful in obtaining potent (pM to low nM IC50 in human cells) LNA ASOs directed against the virus, and focused on one LNA ASO that exhibited exceptional activity in blocking viral replication in human cells. This LNA ASO was found to prevent SARS-CoV-2 viral replication in the K18-hACE2 mouse model when introduced intranasally, without formulation or delivery agents. Indeed, once daily intranasal administration of the LNA ASO in saline effectively (~98-99%) blocked lung infection of all variants of concern tested, including alpha, beta, delta, and omicron variants. These studies provide strong support for the feasibility of using ASOs to target SARS-CoV-2 and other RNA viruses of pandemic potential.
Featured publication:
Wang L, Sinnott-Armstrong N, et al…, Näär AM.
A microRNA linking human positive selection and metabolic disorders
CELL 2020. 183: 684-701.
Antisense oligonucleotides to target microRNA associated diseases
Employing genome wide association studies (GWAS), we have identified multiple microRNAs of interest, namely miR-33 and miR-128-1, as crucial regulators of lipid homeostasis in the body.
We uncovered miR-33a/b as intronic microRNAs present in the SREBP genes that act in concert with the host genes to govern cholesterol/lipid homeostasis. Based on potent effects of antisense oligonucleotides (ASOs) targeting miR-33a/b on atherosclerosis in rodent models, we are currently pursuing state-of-the art locked nucleic acid (LNA) ASO technologies as novel and safe treatments for familial hypercholesterolemia and other cardiovascular diseases.
miR-128- 1 is located in a genomic region on human chromosome 2 that is also strongly linked to recent positive selection, type 2 diabetes, and obesity. Based on our supportive in vivo data in several mouse obesity and metabolic disease models, we hypothesize that miR-128-1 represents a thrifty microRNA that acts as a potent negative regulator of energy expenditure, selected as a human evolutionary adaptation to promote fat storage to survive famine in ancient times. Currently, this represents a maladaptation in the developed world with abundant food, resulting in increased risk for cardio-metabolic diseases such as coronary artery disease, Metabolic Syndrome (MetS), obesity, type 2 diabetes, and non-alcoholic fatty liver diseases (NAFLD/NASH). We have also unexpectedly found a link of miR-128-1 to Duchenne Muscular Dystrophy (DMD), a rare and early lethal muscle wasting disorder, and we are investigating a potential pathological disease modifying role of miR-128-1 in DMD, and whether it might represent a target for LNA ASOs as a novel DMD treatment.
Featured publication:
Yang F, Vought BW, et al.., Näär, AM.
An ARC/Mediator subunit required for SREBP regulation of cholesterol and fatty acid homeostasis.
Nature 2006. 442:700-704.
Mechanistic insights to combat metabolic dysregulation in disease pathology
Another focus of the Näär lab is to elucidate transcriptional and microRNA regulatory mechanisms governing cholesterol/lipid and metabolic homeostasis. Our studies over the last 20 years of the sterol- regulatory element-binding protein (SREBP) family of transcription factors, master regulators of cholesterol/lipid synthesis and trafficking, have led to an atomic-level understanding of the molecular mechanism of SREBP gene regulation. We have parlayed this detailed mechanistic knowledge to guide small molecule therapeutic targeting efforts resulting in the development of nanomolar inhibitors of the interaction of SREBPs with transcriptional co-activators. Ongoing NMR structure-guided medicinal chemistry efforts are aimed at further improving on these inhibitors, with the goal of identifying effective therapeutic modalities as treatments for diseases linked to abnormal cholesterol/lipids and metabolism, including many types of cancers, as well as metabolic syndrome, type 2 diabetes, and cardiovascular disease. Our work is innovative as it challenges the prevalent dogma that protein-protein interactions are not druggable.
Photo of Chi Zhu at lab bench, June 2021 (courtesy of Brittany Hosea-Small)
Research photos of unpublished data (courtesy of Näär lab team)