Dataset Information

Characterization of Human Melanoma Skin Cancer Models: Paving the Way for Model-Based Melanoma Research and Drug Discovery

ABSTRACT: Characterization of Human Melanoma Skin Cancer Models: Paving the Way for Model-Based Melanoma Research and Drug Discovery

PROVIDER: PRJNA1070660 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27765842_1.fastq.gz	Fastqsanger.gz
	SRR27765842_2.fastq.gz	Fastqsanger.gz
	SRR27765843_1.fastq.gz	Fastqsanger.gz
	SRR27765843_2.fastq.gz	Fastqsanger.gz
	SRR27765844_1.fastq.gz	Fastqsanger.gz

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Project description:A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.A robust system using disease relevant cells to systematically evaluate the role in diabetes for loci identified through genome wide association studies (GWAS) is urgently needed. Toward this goal, we created isogenic mutant human embryonic stem cell (hESC) lines in GWAS-identified candidate diabetes genes including CDKAL1, KCNQ1 and KCNJ11, and used directed differentiation to evaluate the function of derivative human beta-like cells. The mutations did not affect the generation of insulin+ cells, but impaired insulin secretion both in vitro and in vivo, coinciding with defective glucose homeostasis. CDKAL1-/- insulin+ cells also displayed hypersensitivity to lipotoxicity. A high-content chemical screen identified a candidate drug that rescued CDKAL1-/--specific defects by inhibiting the AP1 (FOS/JUN) pathway. These studies establish a platform using isogenic hESCs to evaluate the function of GWAS-identified loci, and identify a drug candidate that rescues gene-specific defects, paving the way to precision therapy of metabolic diseases.

Dataset Information

Characterization of Human Melanoma Skin Cancer Models: Paving the Way for Model-Based Melanoma Research and Drug Discovery

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