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Project Title
"Fortalecimiento y desarrollo de la investigación biomédica mediante la adquisición de un cluster computacional"
Partner Organisations
Internal ID
EQM150093
Principal Investigator
LUIS EDGARDO LEON PAREDES
Status
TERMINADO
Start Date
15 December 2015
End Date
17 June 2015
Investigators
Nancy Perez

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Publication

Identification of genetic modifiers of murine hepatic β-glucocerebrosidase activity

2021 , Anyelo Durán , Boris Rebolledo-Jaramillo , Valeria Olguin , Marcelo Rojas-Herrera , Macarena Las Heras , CALDERON GIADROSIC, JUAN FRANCISCO , Silvana Zanlungo , David A. Priestman , Frances M. Platt , KLEIN POSTERNACK, ANDRES DAVID

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Exome Sequencing Identifies Genetic Variants Associated with Extreme Manifestations of the Cardiovascular Phenotype in Marfan Syndrome

2022 , Yanireth Jimenez , Cesar Paulsen , Eduardo Turner , Sebastian Iturra , Oscar Cuevas , Guillermo Lay-son , REPETTO LISBOA, MARIA GABRIELA , Marcelo Rojas , CALDERON GIADROSIC, JUAN FRANCISCO

Marfan Syndrome (MFS) is an autosomal dominant condition caused by variants in the fibrillin-1 (FBN1) gene. Cardinal features of MFS include ectopia lentis (EL), musculoskeletal features and aortic root aneurysm and dissection. Although dissection of the ascending aorta is the main cause of mortality in MFS, the clinical course differs considerably in age of onset and severity, even among individuals who share the same causative variant, suggesting the existence of additional genetic variants that modify the severity of the cardiovascular phenotype in MFS. We recruited MFS patients and classified them into severe (n = 8) or mild aortic phenotype (n = 14) according to age of presentation of the first aorta-related incident. We used Exome Sequencing to identify the genetic variants associated with the severity of aortic manifestations and we performed linkage analysis where suitable. We found five genes associated with severe aortic phenotype and three genes that could be protective for this phenotype in MFS. These genes regulate components of the extracellular matrix, TGFβ pathway and other signaling pathways that are involved in the maintenance of the ECM or angiogenesis. Further studies will be required to understand the functional effect of these variants and explore novel, personalized risk management and, potentially, therapies for these patients.

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Proteomic Analysis of Niemann-Pick Type C Hepatocytes Reveals Potential Therapeutic Targets for Liver Damage

2021 , Elisa Balboa , Tamara Marín , Juan Esteban Oyarzún , Pablo S. Contreras , Robert Hardt , Thea van den Bosch , Alejandra R. Alvarez , Boris Rebolledo-Jaramillo , Andres D. Klein , Dominic Winter , Silvana Zanlungo

Niemann-Pick type C disease (NPCD) is a lysosomal storage disorder caused by mutations in the NPC1 gene. The most affected tissues are the central nervous system and liver, and while significant efforts have been made to understand its neurological component, the pathophysiology of the liver damage remains unclear. In this study, hepatocytes derived from wild type and Npc1−/− mice were analyzed by mass spectrometry (MS)-based proteomics in conjunction with bioinformatic analysis. We identified 3832 proteins: 416 proteins had a p-value smaller than 0.05, of which 37% (n = 155) were considered differentially expressed proteins (DEPs), 149 of them were considered upregulated, and 6 were considered downregulated. We focused the analysis on pathways related to NPC pathogenic mechanisms, finding that the most significant changes in expression levels occur in proteins that function in the pathways of liver damage, lipid metabolism, and inflammation. Moreover, in the group of DEPs, 30% (n = 47) were identified as lysosomal proteins and 7% (n = 10) were identified as mitochondrial proteins. Importantly, we found that lysosomal DEPs, including CTSB/D/Z, LIPA, DPP7 and GLMP, and mitocondrial DEPs, AKR1B10, and VAT1 had been connected with liver fibrosis, damage, and steatosis in previous studies, validiting our dataset. Our study found potential therapeutic targets for the treatment of liver damage in NPCD.

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