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NIH Awards $2.3M in microRNA Research Grants in July

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July has proven to be a big month for microRNAs at the National Institutes of Health, which handed out more than $2.3 million in grants to fund research into both the basic science of the small, non-coding RNAs and their roles in various disease states.

Two of the grants were awarded to support studies of the role of miRNAs in cancer, including one that went to Ohio State University’s Carlo Croce, who is investigating whether the ncRNAs can be used in the early detection and prevention of lung cancer.

In 2011, Croce and colleagues published the results of a study examining the miRNA signatures in lung tumors, normal lung tissue, and plasma samples of more than 1,000 long-term tobacco smokers, which identified expression patterns with strong predictive, diagnostic, and prognostic potential.

With the help of the NIH, Croce aims to further validate the miRNA signatures using NanoString technology and deep sequencing in large patient cohorts available at New York University and the National Cancer Institute of Italy, he wrote in his grant’s abstract.

He is also planning to study the dysregulation of larger non-coding RNAs in lung tumors, normal tissues, and plasma in the same patients in an effort to identify other cancer biomarkers.

Croce’s grant began on July 2 and runs until June 30, 2018. It is worth $967,089 in its first year.

The other cancer-related grant was awarded to Xinan Yang of the University of Chicago to further her investigation into the interactions between miRNAs and their targets in acute myeloid leukemia.

According to her grant’s abstract, it is believed that AML’s high relapse rate is linked with a rare population of leukemic stem cells that display extensive proliferative and self-renewal potential, as well as chemoresistance.

As such, Yang and her team are working to study the interplay between leukemic stem cell-characterized transcription factors and miRNAs in heterologous AML cells.

Using two mathematical methodologies — functional analysis of individual microarray expression, or FAIME, and the mechanism-anchored phenotypes-penotype network, or PGNet — the researchers plan to better understand the biology of the cancer stem cells, focusing on deregulation affected by transcription factor/miRNA interactions, according to the abstract. The findings of these experiments will then be correlated to AML patient outcomes.

Finally, Yang and her collaborators want to develop novel approaches to computationally modeling the interactions between leukemic stem cell regulators and potentially prognostic gene targets.

Her grant runs from July 1 until June 30, 2015, and is worth $203,415 in its first year.

Beyond Cancer

Also pulling in NIH support is Beiyan Zhou, a Texas A&M University researcher studying the effect of miRNAs on macrophage-regulated adipose tissue inflammation, a contributing factor to insulin resistance-associated disorders such as type 2 diabetes.

Chronic nutrient excess is known to cause these macrophages to undergo a “distinct phenotypic switch,” known as macrophage polarization, from one that is anti-inflammatory in lean tissues to one that is pro-inflammatory in obese tissues, according to her grant’s abstract.

Zhou and her colleagues recently reported on the discovery that miR-223 is an important regulator of macrophage polarization and protects against diet-induced adipose issue inflammatory responses and systemic insulin resistance.

It is unknown how miR-223 acts in this way, she wrote in the abstract. However, preliminary data from her lab shows that the miRNA is overexpressed when macrophages are activated in their anti-inflammatory state in lean tissue — an effect that is enhanced by a PPAR-gamma agonist — and that suppression of the miRNA in macrophages blunts the effect of the agonist.

Additionally, a genomic survey predicted three PPAR-gamma consensus binding elements upstream of miR-223’s precursor, Zhou noted in the abstract. Thus, she and her team hypothesize that miR-223 is a potent activator of anti-inflammatory macrophages and that a PPAR-gamma/miR-223 circuit exists to control adipose tissue macrophage polarization in chronic nutrient excess-induced adipose tissue inflammation and insulin resistance.

To test this hypothesis, the scientists will examine macrophages with altered miR-223 levels along with PPAR-gamma agonists and inhibitors to better understand the interactions between PPAR-gamma and the miRNA during the macrophage activation process.

The researchers also plan to treat gain- and loss-of-function miR-223 mouse models with PPAR-gamma agonists and antagonists to determine the miRNA’s role in the protective effects of PPAR-gamma against nutrient excess-induced adipose tissue inflammation and insulin resistance.

Lastly, to dissect the PPARgamma-miR-223 pathway, they will identify miR-223 target genes and validate their functions in regulating macrophage polarization and adipose tissue inflammation.

Zhou’s grant began on July 5 and runs until June 30, 2018. It is worth $309,867 this year.

Lakshmi Pulakat at the University of Missouri also secured an NIH grant for her work on miRNAs and cardiovascular disease associated with insulin resistance from overnutrition.

The standard of care for cardiovascular disease involves the use of drugs such as rapamycin to address vascular restenosis and dexamethasone to combat inflammation, she wrote in her grant’s abstract. However, there is evidence that chronic use of these agents worsens insulin resistance, although the underlying mechanism behind this resistance is unknown.

Both drugs inhibit mTOR complex 1, or mTORC1, a nutrient sensor kinase activated in conditions of over-nutrition and implicated in insulin resistance. It has been observed that mTORC1 suppresses miR-29, which in turn inhibits the angiotensin II receptor and cardioprotective molecule AT2R. The miRNA has further been shown to induce insulin resistance and is upregulated in diabetes. Further, miR-29 appears to suppress AT2R.

In light of these findings, Pulakat and her colleagues hypothesize that mTORC1 activation in cases of over-nutrition increases AT2R expression as a cardiovascular protective mechanism by suppressing miR-29.

With funding from the NIH, she and her team will confirm whether rapamycin and dexamethasone disrupt the mTORC1/miR-29/AT2R axis by boosting miR-29 levels and suppressing AT2R, and whether this worsens cardiovascular disease in rat models of obesity, insulin resistance, and hyperinsulinemia.

They then will see whether the AT2R agonist novokinin can restore the axis by regulating miR-29 expression and activating AT2R, thereby providing protection to the animal models.

Pulakat’s grant began on July 3 and runs until the end of April 2018. It is worth $355,414 in its first year.

Meantime, the NIH awarded Michigan State University’s Scott Counts a grant to support his investigation into the neuroprotective effects of two families of miRNAs in the context of Alzheimer’s disease.

In previous microarray and quantitative PCR studies, Counts and his team identified the miR-212/132 and miR-23a/b families as downregulated in the frontal cortex patients with amnestic mild cognitive impairment, he noted in his grant’s abstract.

A review of human miRNA databases showed that the downregulation of either family was predicted to upregulate two targets that interact to mediate neuroprotective cell stress responses: the deacetylase sirtuin 1 and the forkhead transcription factor foxo3a. Follow-on qPCR studies in the same brain samples revealed that mRNA levels of both putative targets were higher in the cognitively impaired patients versus controls.

The data suggest that miRNA-mediated upregulation of the sirt1/foxo3a pathway “represents a compensatory neuroprotective response to mounting disease,” Counts wrote in the abstract.

With the NIH award, he aims to test this hypothesis using human tissue-based molecular, biochemical, and histochemical approaches, as well as mechanistic pathway modeling in human neurons.

The one-year grant runs from July 1, and is worth $217,586 in the first year.

The Basics

The final grant was awarded to Andrew Grimson at Cornell University, who is trying to identify the protein factors involved in miRNA biology.

To do so, he and his colleagues will use RNAi to inhibit each human gene in combination with a novel cell-based screening strategy to pinpoint genes whose inhibition alters miRNA function, according to his grant’s abstract.

With the NIH support, he is also aiming to develop an “improved experimental framework” for target identification that permits the “high-throughput assessment of miRNA target sites in a minimally perturbed endogenous cellular environment,” he wrote.

His grant began on July 1 and runs for hive years. It is worth $292,277 in the first year.

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