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Large-Scale Functional Genomics Screen to Identify Modulators of Human β-Cell Insulin Secretion
Type 2 diabetes (T2D) is a chronic metabolic disorder affecting almost half a billion people worldwide. Impaired function of pancreatic β-cells is both a hallmark of T2D and an underlying factor in the pathophysiology of the disease. Understanding the cellular mechanisms regulating appropriate insul...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773179/ https://www.ncbi.nlm.nih.gov/pubmed/35052782 http://dx.doi.org/10.3390/biomedicines10010103 |
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author | Szczerbinska, Iwona Tessitore, Annamaria Hansson, Lena Kristina Agrawal, Asmita Ragel Lopez, Alejandro Helenius, Marianne Malinowski, Andrzej R. Gilboa, Barak Ruby, Maxwell A. Gupta, Ramneek Ämmälä, Carina |
author_facet | Szczerbinska, Iwona Tessitore, Annamaria Hansson, Lena Kristina Agrawal, Asmita Ragel Lopez, Alejandro Helenius, Marianne Malinowski, Andrzej R. Gilboa, Barak Ruby, Maxwell A. Gupta, Ramneek Ämmälä, Carina |
author_sort | Szczerbinska, Iwona |
collection | PubMed |
description | Type 2 diabetes (T2D) is a chronic metabolic disorder affecting almost half a billion people worldwide. Impaired function of pancreatic β-cells is both a hallmark of T2D and an underlying factor in the pathophysiology of the disease. Understanding the cellular mechanisms regulating appropriate insulin secretion has been of long-standing interest in the scientific and clinical communities. To identify novel genes regulating insulin secretion we developed a robust arrayed siRNA screen measuring basal, glucose-stimulated, and augmented insulin secretion by EndoC-βH1 cells, a human β-cell line, in a 384-well plate format. We screened 521 candidate genes selected by text mining for relevance to T2D biology and identified 23 positive and 68 negative regulators of insulin secretion. Among these, we validated ghrelin receptor (GHSR), and two genes implicated in endoplasmic reticulum stress, ATF4 and HSPA5. Thus, we have demonstrated the feasibility of using EndoC-βH1 cells for large-scale siRNA screening to identify candidate genes regulating β-cell insulin secretion as potential novel drug targets. Furthermore, this screening format can be adapted to other disease-relevant functional endpoints to enable large-scale screening for targets regulating cellular mechanisms contributing to the progressive loss of functional β-cell mass occurring in T2D. |
format | Online Article Text |
id | pubmed-8773179 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-87731792022-01-21 Large-Scale Functional Genomics Screen to Identify Modulators of Human β-Cell Insulin Secretion Szczerbinska, Iwona Tessitore, Annamaria Hansson, Lena Kristina Agrawal, Asmita Ragel Lopez, Alejandro Helenius, Marianne Malinowski, Andrzej R. Gilboa, Barak Ruby, Maxwell A. Gupta, Ramneek Ämmälä, Carina Biomedicines Article Type 2 diabetes (T2D) is a chronic metabolic disorder affecting almost half a billion people worldwide. Impaired function of pancreatic β-cells is both a hallmark of T2D and an underlying factor in the pathophysiology of the disease. Understanding the cellular mechanisms regulating appropriate insulin secretion has been of long-standing interest in the scientific and clinical communities. To identify novel genes regulating insulin secretion we developed a robust arrayed siRNA screen measuring basal, glucose-stimulated, and augmented insulin secretion by EndoC-βH1 cells, a human β-cell line, in a 384-well plate format. We screened 521 candidate genes selected by text mining for relevance to T2D biology and identified 23 positive and 68 negative regulators of insulin secretion. Among these, we validated ghrelin receptor (GHSR), and two genes implicated in endoplasmic reticulum stress, ATF4 and HSPA5. Thus, we have demonstrated the feasibility of using EndoC-βH1 cells for large-scale siRNA screening to identify candidate genes regulating β-cell insulin secretion as potential novel drug targets. Furthermore, this screening format can be adapted to other disease-relevant functional endpoints to enable large-scale screening for targets regulating cellular mechanisms contributing to the progressive loss of functional β-cell mass occurring in T2D. MDPI 2022-01-04 /pmc/articles/PMC8773179/ /pubmed/35052782 http://dx.doi.org/10.3390/biomedicines10010103 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Szczerbinska, Iwona Tessitore, Annamaria Hansson, Lena Kristina Agrawal, Asmita Ragel Lopez, Alejandro Helenius, Marianne Malinowski, Andrzej R. Gilboa, Barak Ruby, Maxwell A. Gupta, Ramneek Ämmälä, Carina Large-Scale Functional Genomics Screen to Identify Modulators of Human β-Cell Insulin Secretion |
title | Large-Scale Functional Genomics Screen to Identify Modulators of Human β-Cell Insulin Secretion |
title_full | Large-Scale Functional Genomics Screen to Identify Modulators of Human β-Cell Insulin Secretion |
title_fullStr | Large-Scale Functional Genomics Screen to Identify Modulators of Human β-Cell Insulin Secretion |
title_full_unstemmed | Large-Scale Functional Genomics Screen to Identify Modulators of Human β-Cell Insulin Secretion |
title_short | Large-Scale Functional Genomics Screen to Identify Modulators of Human β-Cell Insulin Secretion |
title_sort | large-scale functional genomics screen to identify modulators of human β-cell insulin secretion |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8773179/ https://www.ncbi.nlm.nih.gov/pubmed/35052782 http://dx.doi.org/10.3390/biomedicines10010103 |
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