Investigating the role of a novel RNA binding protein during dauer in c. Elegans - micrornas (mirnas) are a conserved class of small, endogenous noncoding rnas that regulate gene expression…

The National Institute of Child Health and Human Development awarded The Johns Hopkins University $198,728 on February 1, 2026, under the Child Health and Human Development Extramural Research program (CFDA 93.865) to investigate the role of novel RNA binding proteins during dauer in C. elegans.

The project characterizes how microRNA pathway regulation transitions from supporting developmental gene expression to enabling stress-adaptive gene expression when the nematode enters the dauer stage—a stress-resistant developmental alternative triggered by adverse environmental conditions. The research focuses on two conserved protein interactors of the microRNA-induced silencing complex (MIRISC) discovered in preliminary work: UNK-1 (unkempt) and its binding partner CRI-1 (headcase). The investigator hypothesizes that UNK-1 and CRI-1 promote stress adaptation by interacting with MIRISC to degrade pro-developmental gene targets. The work comprises three specific aims: characterizing direct and indirect interactions between UNK-1, CRI-1, and MIRISC; identifying mRNA targets of UNK-1 and assessing overlap with MIRISC targets; and determining the functional significance of these interactions in stress-adaptive processes.

Performance occurs in Baltimore, Maryland. The period of performance runs from February 1, 2026 through August 31, 2028. The assistance type is a project grant.

Investigating the role of a novel RNA binding protein during dauer in c. Elegans - micrornas (mirnas) are a conserved class of small, endogenous noncoding rnas that regulate gene expression post-transcriptionally. They play critical roles in essential biological processes, including animal growth and development. Dysregulation of the mirna pathway has been implicated in the pathogenesis of various human diseases. Mirnas exert their function through the mirna-induced silencing complex (mirisc), which comprises the argonaute protein (ALG-1 in c. Elegans) and other protein cofactors. The composition of mirisc-and thus its ability to degrade mrna targets-varies based on tissue type and physiological conditions. For example, somatic and germline mirisc recruit distinct cofactors, leading to different outcomes for target mrnas. Mirisc composition also shifts dynamically in response to environmental stress or aging. Under adverse environmental conditions, c. Elegans enters an alternative, stress-resistant developmental stage known as dauer. A key unanswered question in the field is how the mirna pathway rapidly transitions from regulating pro-developmental gene expression to stress-adaptive gene expression during this stage. Our preliminary studies reveal two novel protein interactors of mirisc during dauer: the conserved RNA-binding protein UNK-1 (unkempt) and its binding partner, CRI-1 (headcase). I hypothesize that UNK-1 and CRI-1 are critical for stress adaptation in dauer by interacting with mirisc to promote the degradation of pro-developmental gene targets. I will test this hypothesis in three specific aims: in aim 1, i will characterize the interactions between UNK-1, CRI-1, and mirisc, and determine whether they are mediated by direct protein-protein interactions or indirectly through a shared set of mrna targets. In aim 2, i will identify the mrna targets of UNK-1 and assess their overlap with mirisc targets. Preliminary data indicate that UNK-1 expression is highly upregulated during the dauer stage. In aim 3, i will investigate the regulation of UNK-1 and CRI-1 expression during dauer and evaluate their roles in stress adaptation. The conservation of UNK-1 and CRI-1 across species, including humans, suggests that their role in mirisc regulation during stress may be evolutionarily preserved. This work could provide insights into fundamental processes such as metabolism, aging, and cancer, offering broader implications for understanding stress adaptation in complex organisms.