Elucidating the novel regulatory role of long non-coding RNAs in myeloid inflammatory cell differentiation and function Afsar Naqvi, Ph.D. Abstract: One surprising finding of human genome annotation was the abundance of transcripts with little or no protein coding potential. These non-coding RNAs can be further classified as small (<200 nts) and long (>200 nts) non-coding RNAs (lncRNAs). While small ncRNAs have been extensively studied, the raison d'tre of most of the lncRNAs is largely unknown. To this end, this proposal seeks to catalog the lncRNA profiles in monocyte derived macrophages and dendritic cells. These TLR+, long lived myeloid cells are critical in mounting innate immune responses against pathogens. Excessive activity of these cells has been attributed to various inflammatory disorders including periodontitis, gingivitis, autoimmune diseases, etc. The role of lncRNAs in myeloid cell differentiation and functions remain understudied. In this project we aim to identify regulatory lncRNAs that can control differentiation of monocyte derived macrophages and dendritic cells. Multiple lines of evidence show that dysregulated macrophage polarization is associated with various immune disorders or pathogen infection. To identify lncRNAs that may regulate macrophage plasticity, we will also examine the lncRNA profiles in M1 and M2 polarized macrophages. Our preliminary results show differential as well cell type specific expression of lncRNAs indicating that these non- coding RNAs may play a crucial role in the process. The predicted nuclear and cytoplasmic targets of these candidate lncRNAs will be validated in this study. Impact of lncRNA knockdown of overexpression wll assessed on the regulation of key myeloid cell functions like migration and phagocytosis. Overall, this proposal seeks to fill knowledge gaps in our understanding of the role of lncRNAs in regulating myeloid cell differentiation, plasticity and key functions. The valuable information gained from these studies will be utilized to dissect lncRNA-mediated immunoregulation of myeloid cells with a focus on oral inflammatory diseases.
Human health relies profoundly on the capability of immune cells to elicit adept immune responses. Myeloid inflammatory cells (including monocytes, macrophages and dendritic cells) play major role in the activation and propagation of immune responses. Upon injury, peripheral monocytes infiltrate and differentiate to macrophages and dendritic cells. Identifying the endogenous biomolecules that regulate this process can provide us a better understanding. This proposal will examine the role of long non-coding RNAs (lncRNAs) that are differentially expressed during macrophage and dendritic cell differentiation. Additionally, we will identify lncRNAs with a potential to regulate inflammatory status (M1 or M2) of macrophages. These findings will likely uncover novel functional role of lncRNAs through which they can modulate differentiation and function of macrophages and dendritic cells. Information gathered from these studies may provide potential candidate therapeutic immunomodulatory RNA targets. Overall, this proposal seeks to fill knowledge gaps in our understanding of lncRNA mediated functional regulation of key inflammatory immune cells.
