Graduation Semester and Year
2023
Language
English
Document Type
Dissertation
Degree Name
Doctor of Philosophy in Chemistry
Department
Chemistry and Biochemistry
First Advisor
Subhrangsu Mandal
Abstract
Inflammation and immune signaling is central to infection and diseases. Growing evidence suggests that along with protein coding genes, long non-coding RNAs (lncRNAs) play a critical role in disease onset, combat, and recovery against pathogen, damaged and self-altered cells. Our lab has been extensively studying the role of lncRNA HOTAIR (HOX transcript antisense intergenic RNA) in gene regulation and epigenetics, and eventually discovered its hidden function regulating inflammation and immune signaling in macrophage, a major type of cell involved in immunity. Previous scholars in our lab have successfully demonstrated lncRNA HOTAIR’s regulatory molecular mechanism elucidating its specific role in cellular process. That paved the path to look for novel regulators of inflammation and immune signaling in human. Since the entire work was previously done on mouse model, and the major challenge working with mouse model was, unlike protein coding genes, lncRNAs are often found not conserved from species to species. Therefore, to find out novel players in inflammation and immune diseases, I focused on the human system. The Chapter 1 gives an overview of immunity, immune system, and macrophage, a brief discussion on major inflammation regulatory signaling pathways like NF-κB (Nuclear factor-κB), MAP kinase (Mitogen‑activated protein kinase), and JAK-STAT (Janus kinase-signal transducers and activators of transcription) signaling pathways. An extensive discussion and literature review is summarized on reported lncRNAs linked to inflammation and immune signaling. To achieve the first step of my goal, I showcased my work on human monocyte derived macrophage stimulated with inflammatory stimuli, LPS (lipopolysaccharide, bacterial endotoxin), a gram-negative bacterial cell wall component. To find out the novel lncRNAs, I unbiasedly stimulated macrophage and performed an RNA-sequencing (RNA-seq). The RNA-seq revealed a series of uncharacterized novel lncRNAs. We named this class of lncRNAs as human Long noncoding inflammation associated RNAs (hLinfRNAs). In Chapter 2, I focused on studying the top expressing lncRNA, uncovered its function as a regulator of cytokine expression. The Chapter 3 is focused on characterizing an another lncRNA, hLinfRNA3, which was found to be regulated by JAK-STAT signaling pathway despite of being induced by LPS (an NF-κB signaling pathway stimulant). Knockdown study indicating its function in regulating STAT3 response gene, like SOCS3 (suppressor of cytokine signaling 3), suggesting its potential involvement in JAK-STAT signaling pathway. In Chapter 4, I extended my study into inflammatory disease model such as Alzheimer's disease (AD), majorly caused by accumulation of amyloid-beta (Aβ-peptide) peptide plaque in AD patients’ brain. Both in vitro and in vivo study in mice and rat showed that lncRNA HOTAIR is involved in Aβ mediated neuroinflammation, and its potential role in disease progression. The hLinfRNAs are also found upregulated in Aβ stimulated human microglia cells, suggesting their potential involvement in neuroinflammation. Overall, my research has discovered novel players of inflammation and immune signaling in human. This may provide a more in-depth scientific understanding and may offer novel diagnostic and therapeutic approaches.
Keywords
lncRNA, p Macrophage, Inflammation, Immune signaling, hLinfRNA, NF-κB signaling pathway, JAK-STAT signaling pathway, LPS, lncRNA HOTAIR, RNA-seq
Disciplines
Chemistry | Physical Sciences and Mathematics
License
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Chini, Avisankar, "Long non-coding RNAs in inflammation, macrophage activation, and inflammatory human diseases" (2023). Chemistry & Biochemistry Dissertations. 247.
https://mavmatrix.uta.edu/chemistry_dissertations/247
Comments
Degree granted by The University of Texas at Arlington