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(NBU-0830) Platelet TGF-ß1 in Systemic Sclerosis


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A proposal to search for evidence of active platelet-derived TGF-ß1 and its impact on leukocytes in Systemic Sclerosis

Principal Investigator:
Nathalie Burg

Investigators:

Contact Information:
Recruitment Specialist
1230 York Avenue
New York, NY 10065
Telephone: 18007822737
Alt. Telephone: 18007822737
Email: rucares@rockefeller.edu
Enrollment Status:
Closed to Enrollment

Brief Summary of Protocol:
Transforming growth factor-ß1 (TGF-ß1) is a protein that plays an important role in many auto-immune disorders (diseases that arise from an overactive immune response of the body against substances and tissues normally present in the body), including Systemic Sclerosis (SSc). SSc is a connective tissue disease that involves changes in the skin, blood vessels, and internal organs. Platelets are very small cell like particles that are important for proper clotting of blood. These platelets contain a very high concentration of TGF-ß1. The purpose of this study is to understand the role that blood platelets and TGF-ß1 have in the development of SSc.



Detailed Description of Protocol:
Systemic Sclerosis (SSc) is a devastating and often life threatening illness predominantly affecting women characterized by autoimmunity, widespread microvascular disease, and fibrosis, especially of the skin, gastrointestinal tract, and lung. Multiple studies have shown evidence of platelet activation in SSc [1, 2]. Chronic intermittent vasospasm in the microvasculature combined with platelet maggregation and activation may foster an environment in which TGF-?1 is released and activated. Our laboratory has shown that latent TGF-?1, a complex composed of mature TGF- ?1 dimer noncovalently attached to latency associated peptide (LAP) dimer, which in turn is disulfide-bonded to latent TGF-?1 binding protein-1 (LTBP-1), is activated in vitro by shear by a mechanism that includes thiol-disulfide exchange [3]. Latent TGF-?1 is released from most cells and tissues as large latent complexes (LLCs) comprised of LTBP-1, LAP, and TGF-?1. Platelets are the largest source of TGF-?1 in normal blood (45 ng/ml vs 1.5 ng/ml for monocytes) [4]. Since high shear can both induce platelet activation, with release of granule contents, and activate TGF-?1 in vitro, we hypothesize that high shear in the stenotic and compromised microvasculature of SSc patients results in platelet release of latent TGF-?1 as well as other profibrotic, vasoconstrictive, and proinflammatory mediators. The released latent TGF-?1 may then undergo activation, at least in part, by intravascular shear force. In addition, the other released platelet mediators may abet the vascular leak seen in SSc [5] and allow extravasation of leukocytes and egress of both active and latent TGF-?1 into the skin and other affected tissues, where the latter can be stored and/or activated in the extracellular matrix. TGF-?1 signaling is known to induce other cells to produce TGF-?1 in a feed-forward manner. We hypothesize that if targeted early, anti-platelet agents may help diminish inflammation and forestall the pro-fibrotic program in SSc that leads to end-stage organ damage.



What specifically makes a person eligible for the study?
You may be eligible to enter this study:

1. Must have a diagnosis of systemic sclerosis made by a rheumatologist that fulfils ACR criteria for SSc. 2. Cannot have any other rheumatologic diseases 2. Cannot have a history of thrombocytopenia or any other platelet disorder 3. Cannot have any chronic active infection (e.g. hepatitis B, hepatitis C, HIV, etc.) 4. Cannot be receiving hormonal contraception or hormonal replacement therapy 5. Cannot currently be pregnant 6. Cannot have taken anti-platelet medication (e.g. aspirin, non-steroidals, etc.) within the last 7-10 days 7. Cannot have taken warfarin within the last 3 months

Gender:
Both

Age(s):


Children permitted to participate:
No

Potential Benefits.....
compensation is provided



Compensation:
yes