Joint Seminar from Kingsley Lam and Thorben Schlesinger
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Speaker 1: Thorben Schlesinger, NIHR BRC PhD Student
Title: Identifying Targets for Treating HNF1B-associated Kidney Malformations using Human Stem Cell-derived Nephron Organoids
Abstract: Heterozygous mutations in HNF1B are the most common monogenic cause for dysplastic kidney malformations in children. Recently, we found that the kainate type glutamate receptor GRIK3, hitherto unstudied in the kidney, was significantly upregulated in HNF1B-mutant hPSC-derived nephron organoids. For this project, I am using lentiviral vectors encoding GRIK3-targetting shRNAs to restore normal GRIK3 expression in mutant nephron organoids to identify novel targets for treating HNF1B-associated kidney malformations.
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Speaker 2: Kingsley Lam, NIHR BRC PhD Student
Title: Using patient-derived iPSC to characterise Perrault Syndrome
Abstract: Perrault syndrome (PS) is an autosomal recessive disorder characterised by sensorineural hearing loss in both sexes and primary ovarian insufficiency in females with a 46,XX karyotype. Despite several decades since its discovery, the low prevalence and genetic heterogeneity of PS have hindered efforts to elucidate the complex relationship between its genetic basis and diverse clinical phenotypes. This project focuses on a specific molecular subtype, Perrault syndrome type 3 (PRLTS3), caused by biallelic pathogenic variants in the CLPP gene. CLPP encodes caseinolytic peptidase P (ClpP), a mitochondrial protease with a conserved role in the mitochondrial unfolded protein response (mtUPR), mitochondrial dynamics, and mitochondrial DNA homeostasis. Due to the inaccessibility of human auditory neurons, this study aims to develop a relevant neuronal model that recapitulates the genetic background of patients, enabling the screening of approved drugs. Here, we present the progress of this work, including the generation of patient-derived induced pluripotent stem cells (iPSCs) carrying homozygous and heterozygous CLPP p.(Thr145Pro) variants from dermal fibroblasts, CRISPR–Cas9-mediated gene editing, characterisation of the iPSCs, and evaluation of spiral ganglion neuron (SGN) differentiation protocols.