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Collagen production is central to kidney biology, and its overproduction is a hallmark of chronic kidney disease and fibrosis. Understanding how collagen expression is controlled has the potential to reveal new therapeutic directions, but this area remains relatively unexplored. The expected breakthrough discovery of our proposal will be (1) to demonstrate that the very act of producing collagen protein feedbacks to repress its expression and (2) to determine the key molecular pathways involved in its repression. Our overarching rationale for this project builds on three fundamental results in the field of posttranscriptional gene regulation. First, we know that dipeptide motifs like glycine-proline (GP) or PG are challenging for the ribosome and slow down translation elongation. Second, there are two main posttranscriptional pathways that recognize slow or stalled translation and then repress gene expression. Third, collagen is rife with such motifs; indeed, COL1A1 has 306 such motifs. We hypothesize that the translation of collagen is inherently challenging and slow, and thus collagen transcripts naturally are repressed by these two pathways. Here, we propose to test this hypothesis, and we expect to determine a new mechanism regulating collagen production. This discovery matters because it will reveal hitherto unknown pathways that control collagen expression. This discovery will spark new directions and research in the field. For instance, how do kidney cells accommodate the intrinsic challenge of translating collagen? Do professional collagen-producing cells, like fibroblasts, tamp down these repressive pathways to enable higher collagen production? Are these pathways similarly altered during fibrosis? If so, which factors are affected? Our results will form a launching pad for investigating these questions. This line of investigation has the potential to open the door to new therapeutic directions. For instance, messenger RNA-based drugs could enhance repressive pathways to inhibit collagen production for the treatment of kidney fibrosis. Alternatively, inhibiting these pathways through small interfering RNAs or CRISPR could help promote collagen expression. Thus, our proposed research will lead to new ways to modulate collagen production and, in the long-term, hopefully lead to new therapeutic directions to treat chronic kidney diseases.
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