Skip to main content

NIH Awards $800K to Fund Research into microRNAs and Cardiac Disease

Premium

The National Institutes of Health this month awarded more than $800,000 in research funding to support the work of four researchers, including two that have collaborated with Regulus Therapeutics, who are examining the role of microRNAs in various aspects of cardiovascular disease.

The first grant was awarded to New York University School of Medicine's Kathryn Moore to fund her work into miRNAs as physiological and pathological regulators of cholesterol homeostasis.

"The metabolism of cholesterol, an essential cell membrane component and precursor in metabolic pathways, is tightly regulated at both the cellular and organismal level," she wrote in her grant's abstract. Despite the effect of insufficient or excessive cholesterol levels on human health, how the processes of cholesterol influx and efflux are coordinated are poorly understood.

Hypothesizing that miRNAs may influence the epigenetic regulation of cholesterol metabolism pathways, Moore and colleagues previously performed an unbiased genome-wide screen of miRNAs modulated by cellular cholesterol content, identifying ones that target components of the pathways regulating low-density lipoprotein and high-density lipoprotein.

And in 2011, she and collaborators from Regulus authored a paper in Nature showing that inhibition of miR-33a and miR-33b raised HDL levels in non-human primates while lowering levels of very-low-density lipoprotein-associated triglycerides.

With the new NIH funding, she aims to further explore the role of various miRNAs in cholesterol regulation, specifically inhibiting and overexpressing the small, non-coding RNAs to assess their role in regulating lipoprotein metabolism and "determine their impact on atherosclerosis progression and regression," according to the abstract.

The grant began on Dec. 1 and runs until the end of Nov. 2015. It is worth $403,410 in its first year.

Also securing an NIH grant is Yale University researcher Carlos Fernandez-Hernando, who is studying the role of miRNAs in lipid metabolism and cardiovascular disease.

Like Moore, Fernandez-Hernando and his team have generated data linking miR-33a and miR-33b are located within the sterol regulatory element-binding protein 2 and 1 genes, respectively, and that they work to regulate lipid homeostasis with their host genes.

Also in collaboration with Regulus, he later reported that silencing miR-33 inhibited the progression of atherosclerosis in mouse models.

Hypothesizing that "inhibition of miR-33 may represent a therapeutic target for ameliorating cardiometabolic disease, including atherosclerosis and metabolic syndrome," he and his colleagues aim to use the NIH funding to "determine the molecular mechanism underlying the miR-33-mediated responses" in the disorder, according to his grant's abstract.

Specifically, they will use their funding to "delineate the role of miR-33 in regulating cholesterol metabolism, oxidation of fatty acid, and insulin signaling … and to define the role of miR-33 in lipid metabolism, insulin signaling, and atherosclerosis in vivo," the abstract states.

The grant began on Dec. 1 and runs for two years. It is worth $359,382 in the first year.

Rutgers University's Maha Abdellatif was also awarded two NIH grants, which will fund her research into the role of miRNAs in cardiac cell death and cardiac hypertrophy.

She and colleagues previously reported that miR-21, which is upregulated during hypertrophic and cancerous cell growth, is downregulated in cardiac myocytes deprived of oxygen. Further examination showed that the miRNA regulates phosphatase and tensin homologues deleted on chromosome 10, directly targets Fas ligand, and that its downregulation is necessary for enhancing the expression of the two proteins during hypoxia.

"We also observed that activated AKT suppresses the expression of PTEN and FasL in myocytes and induces upregulation of miR-21," she wrote in her grant's abstract.

Building on these findings, she and her team generated a cardiac-specific miR-21 transgenic mouse model that experienced complete suppression of PTEN and FasL expression, smaller infarct size, and less fibrosis and chamber dilatation following chronic coronary artery occlusion, according to the abstract.

With her first NIH grant, Abdellatif plans to examine the upstream pathways and mechanisms involved in the regulation of miR-21, as well as its functional significance. She also aims to study how the miRNA functions along with its target genes in cardiac myocytes, and the miRNAs regulation in vivo.

This grant began on Dec. 1 and runs for two years. It is worth $47,700 the first year.

Her second grant relates to her work with miR-1, which she and colleagues have found to be downregulated upon the induction of hypertrophy from work overload, growth factors, or Ras GTPase-activating protein.

"Our preliminary data show that RasGAP SH3-binding protein binds miR-1 in a RasGAP- and Akt-dependent manner," Abdellatif wrote in the grant's abstract. "We hypothesize that hypertrophic stimuli induce Akt-mediated G3BP phosphorylation and its subsequent recruitment by RasGAP-filamin complex. This brings it into close proximity to miR-1, where it binds and hydrolyzes premature miR-1."

As such, downregulation of miR-1 results in upregulation of targets including RasGAP, Cdk9, fibronectin, endothelin, and insulin-like growth factor — all of which play a role in cardiac hypertrophy.

To further examine this, Abdellatif and her colleagues plan to study the mechanism of RasGAP-mediated down-regulation of miR-1 during myocyte hypertrophy.

Using cultured myocytes in conjunction with recombinant cDNA, adenoviruses, and promoter constructs, they will specifically examine the role of G3BP in post-transcriptional regulation of miR-1; the role of Akt in RasGAP-G3BP-regulated miR-1 stability; the role of filamin-C in recruitment of RasGAP-G3BP; and the effect of hypertrophy and the RasGAP-activated pathway on transcriptional versus post-transcriptional regulation of miR-1, according to the abstract.

They then plan to extend the work to a mouse model of cardiac hypertrophy.

The grant began on Dec. 1 and runs until Nov. 30, 2015. It is worth $50,880 the first year.

The Scan

Pfizer-BioNTech Seek Full Vaccine Approval

According to the New York Times, Pfizer and BioNTech are seeking full US Food and Drug Administration approval for their SARS-CoV-2 vaccine.

Viral Integration Study Critiqued

Science writes that a paper reporting that SARS-CoV-2 can occasionally integrate into the host genome is drawing criticism.

Giraffe Species Debate

The Scientist reports that a new analysis aiming to end the discussion of how many giraffe species there are has only continued it.

Science Papers Examine Factors Shaping SARS-CoV-2 Spread, Give Insight Into Bacterial Evolution

In Science this week: genomic analysis points to role of human behavior in SARS-CoV-2 spread, and more.