The National Institutes of Health this month awarded nearly $2 million in grant funding to support eight research projects investigating the roles of microRNAs in a variety of diseases and biological functions including psychiatric disorders, immune function, glaucoma, and cancer.
The first grant was awarded to Dartmouth College researcher Brock Christensen to support his investigation into miRNA variations that can be used a biomarkers for bladder cancer recurrence and survival.
There is a growing body of research indicating that miRNA-related genetic variations have “critical regulatory capacity” and are associated with both the risk and prognosis of human cancers, according to the grant’s abstract. However, “there is a gap in the study of bladder cancers.”
To help bridge this gap, Christensen and his colleagues aim to use “proven epidemiologic resources” to identify miRNA variations associated with recurrence and survival of bladder cancer.
“Our group has completed a geographically defined, population-based epidemiologic study of bladder cancer that includes a comprehensive assessment of patient recurrences and survival,” he wrote in the abstract. Building off this effort, the team plans to genotype over 18,000 miRNA genetic variations in hopes of identifying a “new class of genetic markers of bladder cancer recurrence and survival that will contribute to the development of clinical decision-making tools to stratify patients into follow-up groups based on their likelihood of recurrence.”
Christensen’s grant runs from April 1 until March 31, 2015, and is worth $50,366 in its first year.
Also receiving NIH funding is Cornell University’s Carla Concepcion, who is exploring the tumor-suppressive functions of the miR-34 family.
This collection of miRNAs has received much attention because it is directly regulated by p53 and can induce cell cycle arrest and apoptosis in vitro, according to the grant’s abstract.
“Importantly, its inactivation has been observed in a number of human cancers.”
Still, the majority of research into the miR-34 family has been done in cell culture or using non-physiologic miRNA expression levels, which can skew results, Concepcion noted. With the help of the NIH grant, she and her colleagues are looking to extend these finding in vivo.
Using constitutive and conditional miR-34 knockout mice already generated in her lab, they will examine whether chronic loss of the miRNA family’s expression promotes tumorigenesis, determine its physiologic role in the p53 pathway, and identify which p53 targets cooperate with the miR-34.
Concepcion’s grant runs from April 1 until March 31, 2016, and is worth $42,232 this year.
A third NIH grant was awarded to MD Anderson Cancer Center’s Keping Xie to help fund his research into miRNA mediators of pancreatic ductal adenocarcinoma, or PDAC, invasion and progression.
In searching for alterations in PDAC gene expression that can be therapeutically targeted, Xie and his colleagues have focused on FoxM1, a transcription factor up-regulated in the disease.
According to the grant’s abstract, they have developed cell lines that over-express FoxM1, finding that they exhibit “greatly elevated growth and metastasis.” Meantime, reduction of FoxM1 expression in PDAC cells inhibits their “aggressive nature.”
In recent studies, Xie’s lab found that most human PDAC cells express a splice form of FoxM1 called FoxM1C, which is not found in normal tissue.
“Based on our preliminary studies, we postulate that during PDAC carcinogenesis, dysregulated miRNA expression leads to over-expression of FoxM1 and [dysregulation of] downstream target genes key to invasion and metastasis, resulting in an enhanced malignant potential of PDAC cells and … poor prognosis of PDAC patients,” he wrote in the grant’s abstract.
To test this hypothesis, the researchers plan to study the mechanisms of action of three miRNAs that have already been computationally identified as targeting FoxM1. They also aim to see whether uPAR, a glycoprotein over-expressed by human pancreatic cells and whose expression levels directly correlate to those of FoxM1, is a downstream target and mediator of FoxM1.
Lastly, they will examine the clinical significance of FoxM1 isoforms in pancreatic cancer invasion and metastasis.
The grant runs from April 1 until March 31, 2018, and is worth $249,000 in the first year.
The NIH also awarded a grant to Allen Gao of the University of California, Davis, to help further his research into the impact of let-7c on androgen receptor activity and prostate cancer.
According to his grant’s abstract, the miRNA, which is known to suppress androgen receptor expression, is down-regulated in prostate cancer cells and tissue. Additionally, a number of studies indicate that this down-regulation occurs via c-myc, an androgen receptor activator that is consistently over-expressed in prostate cancer.
Meantime, let-7c has been shown to inhibit the growth of prostate cancer cells in vitro and in vivo, and analyses of human prostate specimens indicates a reverse correlation between let-7c and androgen expression, the abstract adds.
To further understand the link between let-7c-mediated androgen receptor signaling, Gao will knock down the miRNA in androgen-responsive human prostate cancer cell lines and assess its effect on cell growth and overall androgen responsiveness.
With the NIH funding, he and his colleagues will also look at let-7c over-expression in castration-resistant prostate cancer cells to see if the miRNA can transform the cells to an androgen-responsive state.
To characterize the possible mechanisms of let-7c-mediated androgen receptor suppression and the role of c-myc in this process, Gao and his lab will look at whether the miRNA directly targets c-myc RNA, and test whether the levels of these molecules correlate with disease progression and castration resistance in prostate cancer specimens.
The grant runs from April 1 until March 31, 2018. It is worth $233,759 in its first year.
The final oncology-related grant was awarded to University of Illinois College of Medicine researcher Xiaofeng Zhou, who is studying the impact of miRNAs on oral cancer.
Recent work in his lab points to miRNA dysregulation on the disease, according to his grant’s abstract. “However, the comprehensive microRNA alteration pattern associated with early-stage oral cancer is still lacking, which hindered the potential utilization of microRNA as diagnostic biomarkers.”
Using brush oral cytology, a method that can collect cells from oral lesions for analysis, he and his colleagues will use the NIH funding to identify miRNA signatures associated with early-stage oral cancer. Statistical classification models will then be developed to assess the diagnostic value of the miRNAs.
Zhou’s grant runs from April 1 until the end of March 2015. It is worth $59,813 this year.
University of Southern California researcher Daniel Campbell was awarded a four-year grant from the NIH to support his work on the role of non-coding RNAs in psychiatric disorders, which includes a focus on miRNAs in schizophrenia.
According to the grant’s abstract, miR-137 has been identified in genome-wide association studies as implicated in the disease, with a number of other genes found in such studies proving to be targets of the miRNA. Additionally, over-expression of miR-137 in rat hippocampal neurons leads to a decrease in neurite length, indicating its role in neuronal morphology.
With the support of the NIH, Campbell and his lab aim to see if miR-137 over-expression causes changes in gene expression that affect neuronal function, particularly in combination with MSNP1AS, another ncRNA that has been linked to autism spectrum disorder and affects neuron morphology.
To do so, they will use an RNA-Seq approach to identify those ncRNA transcripts with altered expression in human neuronal cell lines caused by over-expression of miR-137, as well as MSNP1AS, the abstract states.
They also plan to test different approaches for inhibiting the two ncRNAs in human neuronal cell lines, and see if such inhibition affects the neuronal cells’ morphology.
Campbell’s grant began on April 1 and is worth $430,144 in its first year.
The NIH also awarded a two-year grant to Daniela Frasca of the University of Miami School of Medicine, who is studying the effect of miRNAs in B cell responses in the elderly.
“Aging is associated with autonomous defects in B cells, which are important for optimal health because they produce antibodies necessary for responses to vaccines and infectious diseases, as well as other functions,” she wrote in her grant’s abstract. Such defects can affect immunoglobulin class switch recombination, activation-induced cytidine deaminase, and the transcription factor E47.
Preliminary data from Frasca’s lab suggests that certain miRNAs including miR-155 and miR-16 are over-expressed in unstimulated B cells of older adults.
With the NIH grant, she and her team plan to identify additional miRNAs that are up-regulated in unstimulated B cells from elderly individuals, characterize the molecular pathways behind this up-regulation and elucidate their mechanism of action, and test whether oligonucleotides targeting the miRNAs can correct any dysfunction caused by the up-regulation, the abstract states.
To do so, the researchers will sort subsets of B cells and perform miRNA microarray analyses to see which of the non-coding RNAs are up-regulated in connect with activation-induced cytidine deaminase.
The investigators also plan to see if decreased activation-induced cytidine deaminase can be rescued in vitro through the use of miRNA antagonists.
Frasca’s grant began on April 1 and is worth $191,771 in its first year.
The NIH awarded Duke University’s Pedro Gonzalez a four-year grant to support his work looking at miRNA modulation of intraocular pressure, which is elevated in glaucoma patients.
While a number of drugs for lowering intraocular pressure are in clinical testing, they are non-specific, do not restore tissue function, and are dependent on patient compliance, according to the grant’s abstract. “An attractive therapeutic alternative … are molecular therapeutics such as microRNAs that achieve prolonged modulation of various biological functions such as cell contractility because of their ability to regulate entire networks of genes.”
Gonzalez and his colleagues have identified miR-200c as a potential regulator of intraocular pressure based on its ability to inhibit the contractility of cells in the trabecular meshwork that lies around the base of the cornea, and they have shown it to lower intraocular pressure in vivo, he wrote in the abstract.
Meanwhile, the group has developed a new class of viral vectors — including ones based on influenza-associated virus viral-like particles — that appear to sidestep issues with overloading the components of miRNA biogenesis.
To see whether miR-200c can be used therapeutically, Gonzalez and his team aim to assess the role of miRNA on the regulation of cellular contractility of human trabecular meshwork cells, as well as Schlemm’s canal cells, which control the flow of aqueous humor into the bloodstream.
They also plan to examine the effects of miR-200c on aqueous humor outflow function and intraocular pressure in perfused human anterior segments and living rat eyes; and to test whether increased expression of the miRNA can prevent or restore the increase in intraocular pressure in experimental models of glaucoma, the abstract states.
The grant runs from the beginning of April and is worth $425,420 in the first year.