Aberrant splicing in neuromuscular diseases

Project: Research

Description

RNA splicing is a fundamental and very important process required for correct expression of almost all protein coding genes, but its enormous potential for creating diversity in gene expression and its involvement in nearly all disease processes has only recently become widely appreciated (Reviewed in 1,2). A corollary of this diversity is that it requires a high level of flexibility, which makes splicing critically dependent on numerous splicing-regulatory cis-elements throughout our genes and also dependent on the correct expression of the splicing regulatory proteins (trans-factors) that function through the cis-elements. Thus changes (mutations/SNPs) that affect cis-elements in disease genes and/or changes that affect the expression of splicing trans-factors are frequent causes of disease, but the detailed molecular mechanisms and all the involved factors are not known in any disease. A better understanding of the molecular pathology underlying aberrant splicing and how it can be alleviated is therefore fundamental to development of efficient treatments for numerous human diseases. Some therapeutic methods, for instance the use of splicing stimulatory or inhibitory drugs, may be applicable to several diseases, where the splicing defect has a similar molecular pathology. Aberrant splicing is the most significant disease mechanism in the most common neuromuscular diseases. This project focuses on three of the most common neuromuscular diseases: Myotonic dystroph y (DM), spinocerebellar ataxia type 10 (SCA10) and spinal muscular atrophy (SMA)

Layman's description

RNA splicing er en utrolig vigtig, men kompliceret process i ekspressionen af vores gener. Korrekt RNA splicing kræver en meget fin balance mellem splicing regulatoriske elementer (SRE), der findes alle steder i vores gener og fungerer ved at binde mange forskellige splicingsregulatoriske proteiner(SRP). Mutationer der påvirker SRE’er i sygdomsgener fører til forkert splicing og sygdom. Dette er en meget vigtigt mekanisme i nogle af de hyppige neuromuskulære sygdomme og er årsag til myoton dystrofi (DM), spinocerrebellar ataxia type 10 (SCA-10) og spinal muskel atrofi (SMA). Udvikling af behandlinger for disse sygdomme, hvor man korrigerer splicingen vil ikke blot have betydning for disse sygdomme, men også have generel betydning for mange andre sygdomme med aberrant splicing. De to grupper har mangeårig erfaring med neuromuskulære sygdomme og regulering af splicing. Vi ønsker at identificere og karakterisere de involverede SREer i nye og kendte sygdomsgener, samt de involverede SRPer ved disse alvorlige neuromuskulære sygdomme, samt at udnytte denne viden til at identificere allerede godkendte medikamenter (FDA approved), der som ”side effekt” kan korrigere splicingen og dermed få ny anvendelse som terapi ved disse sygdomme. Vi vil udnytte patient celler, minigener og nogle helt nye teknikker, der baserer sig på global sekventering af RNA med SOLEXA sekventering, ligesom vi vil udnytte vores ekspertise RNA baseret i affinitetsoprensning og MS/MS karakterisering. Vores approach er således helt nyt også i international sammenhæng.
StatusFinished
Effective start/end date01/09/200931/08/2012