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Your search keyword '"Apoorva Kotian"' showing total 2 results
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2 results on '"Apoorva Kotian"'

1. Innate immune activation and aberrant function in the R6/2 mouse model and Huntington’s disease iPSC-derived microglia

Author

Julien Gasser, Gaelle Gillet, Jorge S. Valadas, Laura Rouvière, Apoorva Kotian, Wenqiang Fan, James Keaney, and Irena Kadiu

Subjects
microglia, phagocytosis, migration, neuroinflammation, Huntington’s disease, dendritic spines, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Huntington’s disease (HD) is an inherited autosomal dominant neurodegenerative disease caused by CAG repeats in exon 1 of the HTT gene. A hallmark of HD along with other psychiatric and neurodegenerative diseases is alteration in the neuronal circuitry and synaptic loss. Microglia and peripheral innate immune activation have been reported in pre-symptomatic HD patients; however, what “activation” signifies for microglial and immune function in HD and how it impacts synaptic health remains unclear. In this study we sought to fill these gaps by capturing immune phenotypes and functional activation states of microglia and peripheral immunity in the R6/2 model of HD at pre-symptomatic, symptomatic and end stages of disease. These included characterizations of microglial phenotypes at single cell resolution, morphology, aberrant functions such as surveillance and phagocytosis and their impact on synaptic loss in vitro and ex vivo in R6/2 mouse brain tissue slices. To further understand how relevant the observed aberrant microglial behaviors are to human disease, transcriptomic analysis was performed using HD patient nuclear sequencing data and functional assessments were conducted using induced pluripotent stem cell (iPSC)-derived microglia. Our results show temporal changes in brain infiltration of peripheral lymphoid and myeloid cells, increases in microglial activation markers and phagocytic functions at the pre-symptomatic stages of disease. Increases in microglial surveillance and synaptic uptake parallel significant reduction of spine density in R6/2 mice. These findings were mirrored by an upregulation of gene signatures in the endocytic and migratory pathways in disease-associated microglial subsets in human HD brains, as well as increased phagocytic and migratory functions of iPSC-derived HD microglia. These results collectively suggest that targeting key and specific microglial functions related to synaptic surveillance and pruning may be therapeutically beneficial in attenuating cognitive decline and psychiatric aspects of HD.

Published
2023
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2. Ontogeny of small intestinal drug transporters and metabolizing enzymes based on targeted quantitative proteomicsS

Author

Apoorva Kotian, Nico Kist, Rene M. H. Wijnen, Saskia N. de Wildt, Johan Nicolaï, Anna-Lena Ungell, Paul Cutler, Márton Kiss, Frans G. M. Russel, Richard Mbasu, M. G. Mooij, Karin Barnouin, and Pediatric Surgery

Subjects
Adult, Metabolic Clearance Rate, Biological Transport, Active, Pharmaceutical Science, Ileum, Pharmacology, Peptide Transporter 1, digestive system, Jejunum, All institutes and research themes of the Radboud University Medical Center, SDG 3 - Good Health and Well-being, Tandem Mass Spectrometry, Multidrug Resistance Protein 1, Intestine, Small, medicine, ATP Binding Cassette Transporter, Subfamily G, Member 2, Cytochrome P-450 CYP3A, Humans, Glucuronosyltransferase, Child, Enzyme Assays, Organic cation transport proteins, biology, Multidrug resistance-associated protein 2, Peptide transporter 1, Age Factors, Membrane Transport Proteins, Multidrug Resistance-Associated Protein 2, Neoplasm Proteins, Gene Ontology, medicine.anatomical_structure, Monocarboxylate transporter 1, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], Inactivation, Metabolic, biology.protein, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11], Drug metabolism, Chromatography, Liquid
Abstract

Most drugs are administered to children orally. An information gap remains on the protein abundance of small intestinal drug-metabolizing enzymes (DMEs) and drug transporters (DTs) across the pediatric age range, which hinders precision dosing in children. To explore age-related differences in DMEs and DTs, surgical leftover intestinal tissues from pediatric and adult jejunum and ileum were collected and analyzed by targeted quantitative proteomics for apical sodium–bile acid transporter, breast cancer resistance protein (BCRP), monocarboxylate transporter 1 (MCT1), multidrug resistance protein 1 (MDR1), multidrug resistance–associated protein (MRP) 2, MRP3, organic anion–transporting polypeptide 2B1, organic cation transporter 1, peptide transporter 1 (PEPT1), CYP2C19, CYP3A4, CYP3A5, UDP glucuronosyltransferase (UGT) 1A1, UGT1A10, and UGT2B7. Samples from 58 children (48 ileums, 10 jejunums, age range: 8 weeks to 17 years) and 16 adults (8 ileums, 8 jejunums) were analyzed. When comparing age groups, BCRP, MDR1, PEPT1, and UGT1A1 abundance was significantly higher in adult ileum as compared with the pediatric ileum. Jejunal BCRP, MRP2, UGT1A1, and CYP3A4 abundance was higher in the adults compared with children 0–2 years of age. Examining the data on a continuous age scale showed that PEPT1 and UGT1A1 abundance was significantly higher, whereas MCT1 and UGT2B7 abundance was lower in adult ileum as compared with the pediatric ileum. Our data contribute to the deeper understanding of the ontogeny of small intestinal drug-metabolizing enzymes and drug transporters and shows DME-, DT-, and intestinal location–specific, age-related changes. SIGNIFICANCE STATEMENT This is the first study that describes the ontogeny of small intestinal DTs and DMEs in human using liquid chromatography with tandem mass spectrometry–based targeted quantitative proteomics. The current analysis provides a detailed picture about the maturation of DT and DME abundances in the human jejunum and ileum. The presented results supply age-related DT and DME abundance data for building more accurate PBPK models that serve to support safer and more efficient drug dosing regimens for the pediatric population.

Published
2021

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