Establishment of clonal myogenic cells in FSHD

I have found a link to the full article. Maybe this will help to understand a bit about what they are trying to do.
Well lets hope it does!

http://www.skeletalmusclejournal.com/content/pdf/2044-5040-1-12.pdf

Thanks for taking the time to read this, Kristina.

That has made it a bit clearer. It does sound like that it is a pretty important thing that they have been able to do.

I’m assuming they need to do this so that they can test different drugs and treatments and to see how the cells evolve over a matter of time?

I thought they had a mouse model, can not find to much info on it.
A few years ago a FRG1 mouse model was developed. At that time it was thought that this mouse would be a good model of FSHD. Although it has been of some use, it has proved not to be as good as was thought. Now that more recent research has determined that the DUX4 gene in combination with a particular adjacent chromosome arrangement is the cause of FSHD, a new and more appropriate mouse model must be found or developed.

Apparently an American company has had a donnation from the MDA or someone to help develope a Mouse Model for FSHD.
This was towards the end of last year. The reaserch company is called Harper Lab.

2. “Defining the Tissue and Cell Specificity of the Human DUX4 promoter in Mice”
Scott Harper, Ph.D.
Center for Gene Therapy
The Research Institute at Nationwide Children’s Hospital
The Ohio State University
Room WA3015
700 Children’s Drive
Columbus, OH 43205 USA
$50,000 over 1 year

PROJECT SUMMARY

FSHD was formally classified in 1954, and the primary genetic defect, D4Z4 contraction, was identified in 1992, but the pathogenic mechanisms underlying the disease have only recently started to come into focus. One reason for the difficulties in understanding FSHD biology is the lack of a relevant animal model expressing FSHD-permissive D4Z4 arrays. Since animal models, particularly mice, are crucial tools for studying disease pathogenesis and developing potential therapeutics, the absence of an FSHD mouse model is a fundamental problem in the FSHD field. A major goal of the Harper lab is to generate an FSHD mouse model expressing a single FSHD-permissive human D4Z4 repeat, and to use this model to understand the role of the D4Z4-resident gene, DUX4, in FSHD pathogenesis, and develop RNAi therapeutics targeting DUX4.

In preliminary data, supported by previous FSH Society Fellowships to the Harper Lab, we delivered DUX4 to mouse muscle using adenoassociated viral vectors (AAV). DUX4 over-expression in muscle caused myopathy, but DUX4 is generally toxic to many non-muscle cells as well. Thus, we hypothesized that if DUX4 over-expression is an underlying pathogenic event in FSHD, it must be preferentially expressed only in affected muscles. We therefore developed transgenic mice expressing the green fluorescent protein (GFP) gene from the human DUX4 promoter (DUX4p-GFP mice), to determine the tissue and cell specificity of DUX4. In preliminary studies, we observed gross GFP expression in the face, shoulder girdle, and limbs of three independent DUX4p-GFP mouse lines. In this proposal, we will more carefully define the developmental and cellspecific expression patterns of DUX4p-GFP mice, and develop an AAV vector to determine whether a viral-mediated vascular delivery approach can produce the same expression patterns. Ultimately, these studies will be important first steps toward developing an AAV-mediated D4Z4 mouse model.

Specific Aim 1: To define the developmental and cell-specific expression patterns of the human DUX4 promoter in mice. Mounting evidence supports the hypothesis that over-expression of the D4Z4-resident DUX4 gene is an underlying pathogenic event in FSHD. DUX4 is generally toxic to many cell types, and since FSHD is characterized by dystrophy of very specific muscle groups, we hypothesized that DUX4 is preferentially expressed only in affected muscles. Our newly generated DUX4p-GFP reporter mice grossly express GFP in areas that are preferentially affected in FSHD. In this Aim, we will perform a detailed characterization of GFP expression in our DUX4p-GFP mice. These results will help define the expected expression patterns of DUX4, and ultimately increase our understanding about the role of DUX4 FSHD pathogenesis.

Specific Aim 2: To develop an AAV vector-mediated DUX4p-GFP mouse model. Previous endeavors to generate D4Z4 or DUX4 FSHD mouse models using traditional transgenic approaches have been unsuccessful. Although the previous attempts are not published in peer-reviewed literature, the difficulties encountered in generating these models were discussed in abstracts and talks at various scientific meetings over the last several years, including at the FSH Society’s 2008 International Research Consortium and Research Planning Meeting held in Philadelphia, Pennsylvania
Vascular delivery of AAV vectors carrying FSHD-permissive D4Z4 repeats to adult mice may circumvent the early embryonic death or developmental defects arising from germline transmission of D4Z4 repeats using traditional methods. In this Aim, we will test the feasibility of using AAV vectors to drive D4Z4-specific expression patterns in mouse muscle using an AAV.DUX4p-GFP reporter vector.

Heres a link to a list of other reaserch grants and what they are used for, funded in America.
http://www.fshsociety.org/pages/resFellows.html
I could not find one for the UK or Europe. Is there anything like this in the UK? If so could who ever point me in the right direction.

Thanks again Kristin, hope it didnt melt your brain to much!

WW

Thanks for the other info Kristin, it shall keep me busy for a while, but I am always looking for new info so it probably won’t be to long before I am bothering you again!

With regards to a translator, on the new Internet Explorer 9 there is a function where it automatically detects a foreign language on a web page and then translates it into English. Which I think is quite handy if a bit lot lazy!

WW

Thanks Kristin.