Area:
Neuroscience Biology, Genetics, Pharmacology
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High-probability grants
According to our matching algorithm, Marco Boccitto is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2015 — 2017 |
Boccitto, Marco E |
F32Activity Code Description: To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Roles of Ro60 Rnps in Uv Stress and Cutaneous Autoimmunity
? DESCRIPTION (provided by applicant): The Ro60 autoantigen is a ring-shaped RNA binding protein that has been found to play an evolutionarily conserved role in in assisting cell survival following ultraviolet (UV) radiation. Knockout experiments have demonstrated the importance of Ro60 for enhancing survival after UV stress in keratinocytes, but how this is achieved is still unknown. UV radiation has been reported to cause structural changes in non-coding RNAs that may impair their function, and increase expression of repeat derived transcripts, which can be cytotoxic, or cause genomic instability. Although several other RNA binding proteins have also been reported to enhance survival after UV stress, little is known about how cells cope with changes in RNA integrity and composition induced by UV stress. The first goal of this project is to determine if UV stress alters the RNAs bound by Ro60 in keratinocytes, and determine how Ro60 binding influences the homeostasis of these RNAs. These experiments have the potential to uncover a novel pathway used by cells to promote survival after UV insult. Importantly, autoantibodies to Ro60 are strongly associated with the autoimmune dermatitis subacute cutaneous lupus erythematosus (SCLE). Ribonucleoproteins (RNPs), such as Ro60, are targeted by autoantibodies in several autoimmune disorders, and there is evidence that the nucleic acid portion of these RNPs is critical for initiating inflammation by activating toll-like receptors (TLRs). UV light is known to be a major trigger for inflammation in SCLE, therefore the RNAs bound to Ro60 during UV stress are likely to be components of Ro60 RNPs that initiate inflammation in SCLE. Thus, the second goal of this project is to determine if Ro60-bound RNAs in keratinocytes subjected to UV stress are potent TLR activators. The first aim is to determine the extent to which the set of RNAs bound to Ro60 is altered after UV stress in human keratinocytes. This will be achieved by in vivo crosslinking, immunoprecipitation with anti-Ro60 antibodies, and high-throughput sequencing of cDNAs complementary to the Ro60-bound RNAs (HITS-CLIP). HITS-CLIP will be performed with both traditional anti-Ro60 antibodies and SCLE patient sera, to determine whether SCLE patient sera recognizes a specific subset of Ro60 RNPs. The second aim is to use high throughput sequencing to determine the abundance of Ro60 targets after UV stress with and without Ro60 knockdown. This will indicate how Ro60 binding modifies the homeostasis of target RNAs, and provide insight into pathways that mitigate deleterious changes in RNA caused by UV stress. The third aim is to determine if RNAs associated with Ro60 after UV stress are potent activators of TLRs in plasmacytoid dendritic cells (PDCs). RNAs identified in Aim 1 will be presented to PDCs as either naked RNAs or in vitro generated Ro60-containing immune complexes and assayed for their ability to activate TLRs. The experiments in this aim should identify the set of RNAs that are most likely to contribute to inflammation in SCLE. Given their possible centrality in SCLE pathogenesis, these RNAs are potential therapeutic targets.
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