MODULATORS OF SEPSIS · Identification of genetic determinants of sepsis which modulate gene expression
6РП — Действия „Мария Кюри“
- Период
- 2007-03-26 → 2009-03-25
- Финансиране от ЕС
- 169 365 €
- Участници
- 1
- Схема
- IIF
Линиите свързват координатора с партньорите.
Накратко на български
Генетичните варианти в района на MHC (хромозома 6) определят как се променя експресията на гените при сепсис. Разбирането на тези механизми помага да се установи защо някои хора са по-податливи на тежки инфекции от други.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Final Activity Report Summary - MODULATORS OF SEPSIS (Identification of genetic determinants of sepsis which modulate gene expression)
Susceptibility to infectious diseases such as sepsis is in part determined by our individual genetic makeup. Advances in genetics research over recent years have enabled specific gene regions to be identified as likely to be important in determining disease susceptibility, such as the major histocompatibility complex (MHC) on chromosome 6. However, it remains a significant challenge to identify the specific causative genetic variant(s) as there are many different polymorphisms which are often co-inherited (the combination of variants are described as 'haplotypes'). This project sought to complement population genetic studies of infectious disease by identifying functionally important genetic variants which modulate levels of gene expression in the MHC. To do this, large numbers of B cells (lymphoblastoid cell lines) from different people carrying different MHC haplotypes were analysed using a microarray following cell stimulation with endotoxin. The microarray was used to determine regions of the MHC which were important for the control of gene expression by means of a DNase I hypersensitivity site assay. This assay looks at how sensitive regions of DNA are to digestion with the enzyme DNase I. This in turn depends on the state of the chromatin coat found around DNA - in an open chromatin conformation, a state associated with regulatory regions, the DNA is more sensitive to DNase I digestion. This work has generated a novel haplotype-specific DNase I hypersensitivity map of the MHC and identified a number of important novel DNase I hypersensitive sites, including some which are stimulus specific, and some which are haplotype specific.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
Sepsis remains the health-care problem associated with a high mortality despite advances in drug treatment. There is considerable interest in genetic differences between patients, which may modulate the risk of severe sepsis development and outcome. A number of genetic associations have been found in genes involved in the immune and inflammatory pathways. However it remains unclear if the disease-associated genetic polymorphisms are themselves functionally important or serving as a marker for co-inherited regulatory variants on the same haplotype. To identify genetic variation modulating gene expression present on sepsis-associated haplotypes, we propose to study candidate disease-associated genes in a model system and in patients.A cell line model will be used comprising a panel of immortalised human B cells established from different individuals with defined genetic make-up. This will allow us to use a set of haplotypes for expression studies containing disease-associated polymorphisms. A number of stimuli will be used to resolve if haplotype-specific differences in gene expression are present in cell lines. Then candidate functional haplotypes in primary human cells from patients with severe sepsis will be investigated. For disease-associated haplotypes showing differences in expression in both the cell lines and on primary cell analysis we will investigate the underlying functional mechanisms using assays of transcription such as differential protein-DNA binding in vitro and in vivo.This proposal will advance our understanding of how genetic differences between patients can be used to improve outcome of sepsis. It is timely due to the wealth of genetic data becoming available to resolve how genetic variation is co-inherited and will take advantage of state-of -the-art experimental approaches available in the proposed Host Centre to allow resolution of functional effects of variation on gene expression.
Оригинален текст от CORDIS (на английски).
Участници
- THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD · OXFORDКоординаторОбединеното кралство
Връзки
Данни: CORDIS, © Европейски съюз