The primary goal of this proposal is to attain the clinical research skills to become an excellent, independent investigator in the field of rheumatology and continue my strong research and clinical interest in scleroderma. The diverse clinical and research environment in the Division of Rheumatology and the resources at the Johns Hopkins Bloomberg School of Public Heatlh are an ideal setting for this mentored patient-oriented research career development award. Systemic sclerosis is a multisystem disease manifested by cutaneous fibrosis, vascular abnormalities and immunological disturbances that exhibits marked heterogeneity in presentation. Many studies have provided evidence that the microvasculature is the primary site of disturbance in scleroderma, and manifestations of vascular disease are present in nearly every patient. It is clear, however that patients have ongoing sub clinical vascular damage that may eventually result in a catastrophic vascular disease such as pulmonary hypertension. Currently there are no markers to assess this ongoing vascular activity in scleroderma. Recurring episodes of vasospasm can lead to ischemia/reperfusion injury. One of the normal compensatory mechanisms to ischemia-reperfusion injury is new vessel formation or angiogenesis. Defects in the hypoxia-sensing pathways or downstream mediators of angiogenesis could facilitate critical tissue ischemia which may lead to the characteristic pathologic changes present in scleroderma tissues such as vascular remodeling, tissue fibrosis and end-organ damage. We have studied a panel of angiogenesis stimulators and inhibitors in a large cross-section of patients with scleroderma and there are clear differences in this group compared to controls. The main goal of this proposal is to discover whether angiogenesis stimulators and inhibitors may be markers of ongoing vascular disease activity in scleroderma and may serve as a predictor of the development of pulmonary hypertension or other severe vascular consequences when studied prospectively in a large cohort of scleroderma patients.
