Scleroderma target discovery

Systemic sclerosis (SSc), is a chronic systemic autoimmune disease
characterized by fibrosis, vascular alterations, and the presence of
auto-antibodies. This disease is found worldwide with women four times more
likely to develop scleroderma than men. In the Netherlands, approximately 9
persons in 100,000 persons is affected. SSc is classified according to the
American College of Rheumatology (ACR) or LeRoy criteria of early SSc. The
prognosis is relatively good for LcSSc patients but is worse for those with the
DcSSc, particularly in older age, and for males. Death occurs most often from
pulmonary, heart, and kidney complications. Typical SSc is classically defined
as symmetrical skin thickening, with about 90% of cases also presenting with
Raynaud's phenomenon, nail-fold capillary changes, and anti-nuclear antibodies.
Auto-antibodies are important diagnostic tools that can also provide
information about the clinical subset of SSc; anti-topoisomerase antibodies,
like anti-scl70 most often are present in DcSSc, whereas anti-centromere
antibodies are more often observed in LcSSc. Other auto-antibodies can be found
as well, such as anti-U3 or anti-RNA polymerase. The events initiating SSc are
unknown. Although SSc runs in families, disease-related genes have not been
identified yet.

Because the pathophysiology of SSc is unknown, there is currently no treatment
available to cure the disease itself, so only individual organ system
complications are treated (7,8). Therefore, treatment is patient-specific and
aimed at ameliorating symptoms of the disease. This project aims to identify
genes that upon knockdown interfere with SSc-related phenotypes in relevant
human cells. These targets should be amenable for drug discovery and
development, and inhibit or resolve fibrosis in SSc.

The ultimate goal is to identify targets that, upon knockdown, interfere with
SSc-related phenotypes in human fibroblasts by a high throughput shRNA
SilenceSelect®library with 16.800 shRNA targeting ~5.250 genes by Biofocus.
These targets should be amenable for drug discovery and development, and
inhibit or resolve fibrosis in SSc.

Skin biopsies are easily mastered, quick and have a low incidence of infection,
bleeding, non-healing or significant scarring. Blood sampling will occur at the
*Prikpost* B4. Therefore, the risks of this study is limited to a minimal
bruise. The participants do not benefit from this study.