NEW YORK (GenomeWeb) – The National Institutes of Health this month earmarked more than $1 million this month to fund three research projects investigating the potential role of microRNAs in reducing the efficacy of vaccines and radiotherapy, as well as how the small, non-coding RNAs influence the long-term storage of memories.
The first grant was awarded to East Tennessee State University researcher Zhi Yao, who is studying the molecular mechanisms by which chronic viral infections induce premature T cell aging and subsequently blunt immunologic responses to vaccines, with a particular focus on hepatitis B and C.
According to Yao's grant abstract, vaccines given to virus-infected individuals are frequently ineffective, but the exact mechanisms behind this phenomenon are not fully understood. Speculating that T cell dysfunction may be involved, he and his colleagues have recently shown that chronic HCV infection leads to an upregulation of aging markers in these CD4 T cells, as well as a decline in miR-181a levels.
This reduction in miR-181a is associated with the translation of certain genes related to T cell inhibition, while the miRNA's restoration leads to improved T cell responses.
To better understand the relationship between miR-181a and T cell activity, Yao aims to study the epigenetic, transcriptional, and translational mechanisms that control the miRNA's expression in T cells, as well as its role in regulating aging markers, during HCV infection. He and his team will also use the grant funding to further look into how the loss of miR-181a affects responses to vaccines in HCV patients.
"This translational study is significant in that it provides a working model to explore mechanisms that may be fundamental to diminished vaccine responses in general, particularly in the setting of immunocompromise by HIV, hemodialysis, transplantation, and cancer," he wrote.
The grant began on Dec. 1 and runs until Nov. 30, 2019. It is worth $365,000 in its first year.
Also receiving NIH funding is Emory University's Ya Wang, who is investigating the role of miR-21 in tumorigenesis and radioresistance.
This miRNA is well-known to be upregulated in a number of cancer types, and different research groups have shown that its overexpression can induce tumor growth. Meanwhile, there is a small but growing body of evidence suggesting that miR-21 also contributes to a tumor's resistance to radiation therapy.
Recently, Wang and her colleagues found that in human tumor cell lines, miR-21 plays a role in promoting the repair of the DNA double-strand breaks caused by radiotherapy, potentially by stimulating non-homologous end joining and homologous recombination repair.
With her grant from the NIH, Wang hopes to confirm whether miR-21 does, indeed, influence non-homologous end joining, homologous recombination repair, or both. She also aims to uncover the mechanisms by which miR-21 and its targets induce radioresistance in tumors.
"Since miR-21 over-expressed in almost all types of human tumors, the results from this proposal are expected to not only enhance our knowledge of tumor cell radioresistance, but also provide novel targets and pathways for improving tumor radiotherapy," she wrote in her grant's abstract.
Wang's two-year grant began on Dec. 1 and is worth $169,650 in its first year.
The last grant went to Scripps Research Institute scientist Courtney Miller, who is exploring the possibility that miRNAs are involved in helping the brain maintain the structure required for long-lasting memories.
As she noted in her grant's abstract, thousands of mechanisms for how memories are initially formed have been identified, but only three mechanisms behind the brain's storage of memories are known.
"There is a growing consensus that memory is supported by structural and functional plasticity at excitatory synapses on dendritic spines, with tight regulation of the actin cytoskeleton providing the scaffolding," she wrote, adding that miRNAs' ability for bidirectional gene modulation may be one such mechanism.
Preliminary expression profiling data from her lab indicates that miRNAs involved in the regulation of the actin cytoskeleton are persistently altered after learning in the amygdala, the brain's emotional memory center. As such, she hypothesizes that miRNAs contribute to the long-term stability of a memory trace by maintaining learning-induced structural plasticity, and that traumatic memory maintenance may involve the recruitment of additional miRNAs within the amygdala.
With the goal of identifying mechanisms that can be used to erase traumatic memories, she and her team plan to use the NIH funding to study the effects of persistent miRNA changes on the maintenance of a 30-day old memory and structural plasticity of neurons, as well as the functional impact of persistent miRNA changes unique to the maintenance of a traumatic memory, according to the grant's abstract.
Miller's grant began on Dec. 1 and runs for five years. It is worth $472,500 in its first year.