Dataset Information

An isobaric labeling approach to enhance detection and quan-tification of tissue-derived plasma proteins as potential early disease biomarkers

ABSTRACT: Accurate detection and quantification of low abundance proteins by standard mass spectrometry approaches remains challenging. In addition, it is difficult to link low abundance plasma proteins back to their specific tissues or organs of origin with confidence. To address these challenges, we developed a mass spectrometry approach based on the use of tandem mass tags (TMT) and a tis-sue reference sample.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Papio Anubis Anubis Papio Hamadryas Adenovirus 1

TISSUE(S): Blood Plasma, Kidney

SUBMITTER: Sumaiya Nazli

LAB HEAD: Michael Olivier

PROVIDER: PXD039430 | Pride | 2023-03-11

REPOSITORIES: Pride

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Publications

An Isobaric Labeling Approach to Enhance Detection and Quantification of Tissue-Derived Plasma Proteins as Potential Early Disease Biomarkers.

Nazli Sumaiya S Zimmerman Kip D KD Riojas Angelica M AM Cox Laura A LA Olivier Michael M

Biomolecules 20230122 2

The proteomic analysis of plasma holds great promise to advance precision medicine and identify biomarkers of disease. However, it is likely that many potential biomarkers circulating in plasma originate from other tissues and are only present in low abundances in the plasma. Accurate detection and quantification of low abundance proteins by standard mass spectrometry approaches remain challenging. In addition, it is difficult to link low abundance plasma proteins back to their specific tissues ...[more]

PMID: 36830584

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Project description:The transcriptional regulation of drug-metabolizing enzymes and transporters (here collectively referred to as DMEs) in the developing proximal tubule is not well understood. As in the liver, DME regulation in the PT may be mediated through nuclear receptors which are thought to “sense” deviations from homeostasis by being activated by ligands, some of which are handled by DMEs, including drug transporters. Systems analysis of transcriptomic data during kidney development predicted a set of upstream transcription factors, including Hnf4a and Hnf1a, as well as Nr3c1 (Gr), Nfe2l2 (Nrf2), Ppara, and Tp53. Motif analysis of cis-regulatory further suggested that Hnf4a and Hnf1a are the main transcriptional regulators in the PT. Available expression data from tissue-specific Hnf4a KO tissues revealed that distinct subsets of DMEs were regulated by Hnf4a in a tissue-specific manner. ChIP-seq was performed to characterize the PT-specific binding sites of Hnf4a in rat kidneys at three developmental stages (prenatal, immature, adult), which further supported a major role for Hnf4a in regulating PT gene expression, including DMEs. In ex vivo kidney organ culture, an antagonist of Hnf4a (but not a similar inactive compound) led to predicted changes in DME expression, including among others Fmo1, Cyp2d2, Cyp2d4, Nqo2, as well as organic cation transporters and organic anion transporters Slc22a1(Oct1), Slc22a2 (Oct2), Slc22a6 (Oat1), Slc22a8(Oat3), and Slc47a1(Mate1). Conversely, overexpression of Hnf1a and Hnf4a in primary mouse embryonic fibroblasts (MEFs), sometimes considered a surrogate for mesenchymal stem cells, induced expression of several of these proximal tubule DMEs, as well as epithelial markers and a PT-specific brush border marker Ggt1. These cells had organic anion transporter function. Taken together, the data strongly supports a critical role for HNF4a and Hnf1a in the tissue-specific regulation of drug handling and differentiation toward a PT cellular identity. Hnf4a binding was examined in rat kidneys at three timepoints (E20, P13 and Adult) and p300 binding was examined in adult rat kidney cortex tissue using ChIP-seq. Four corresponding input DNA samples were used as controls for peak calling.

Dataset Information

An isobaric labeling approach to enhance detection and quan-tification of tissue-derived plasma proteins as potential early disease biomarkers

Publications

An Isobaric Labeling Approach to Enhance Detection and Quantification of Tissue-Derived Plasma Proteins as Potential Early Disease Biomarkers.

Similar Datasets

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