- Friday, January 27, 2023
- 2:00 PM–2:50 PM
- SB 010
Calvin students present research from their summer internships
Targeting Histone Reader ENL with PROTAC Degrader
Josiah Harsh
ENL is a histone reader that is part of the super elongation complex and is primarily involved in chromatin and gene expression regulation. ENL is essential for the progression of a spectrum of acute myeloid leukemia (AML), and some hotspot mutations of its reader module YEATS domain have been found to be oncogenic. For this reason, we explored the efficacy of a newly developed ENL PROTAC degrader in its ability to degrade wild-type and mutant ENL protein and suppress oncogene expression in cancer cells. We believe the PROTAC degrader being tested is effective given its successful degrading of wild-type and mutant ENL, downregulation of cancer stem cell (CSC) genes, and inhibition of cancer cell growth.
Steroid Profiling of Low-Renin and Primary Hypertension
Elizabeth Harsh
Hypertension affects about 50% of the US adult population, and low-renin hypertension (LRH) may affect up to 20% of patients with hypertension. Causes of LRH include primary aldosteronism and other forms of inappropriate activation of mineralocorticoid receptors (MR). Cortisol is a potent MR agonist, but physiologic concentrations of cortisol are inactivated to cortisone by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (HSD11B2), which is present in MR-expressing tissues. Beyond primary aldosteronism and Cushing syndrome, other forms of LRH can be caused by other direct MR agonists, or by HSD11B2 inhibitors, such as licorice or glycyrrhetinic acid-like factors (GALFs). The latter facilitates MR activation by physiologic concentrations of cortisol. Inappropriate MR activation is associated with a higher risk of cardiovascular and renal complications and increased mortality. Our project sought to identify circulating biomarkers of LRH. We used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify twenty-three steroids in morning sera from fifty patients with LRH and fifty patients with primary hypertension. We found differences in the steroid profiles of patients with LRH vs primary hypertension. Steroids of interest will be tested in an in vitro model for MR agonism vs HSD11B2 inhibition, in hopes that mechanisms of MR activation alternative to aldosterone might help design customized hypertension therapies.
