Systemic Sclerosis (SSc) is characterized by heterogeneous disease manifestations and variations in disease prSystemic sclerosis (SSc) presents special problems for developing therapies due to the heterogeneous clinical presentation, the variability of disease progression and the difficulty quantifying the extent of disease. Heterogeneous disease progression makes it impossible with currently available clinical tools to tell whose skin and internal organ disease is going to progress, and whose is going to stabilize or improve spontaneously. We have recently shown that expression of four genes in the skin correlates highly with the modified Rodnan skin score (MRSS), suggesting that markers for disease progression, predicting future changes in the MRSS, might also be identified with the proper clinical/pathological samples. The major focus of the first aim in this proposal is to identify such biomarkers. We propose two approaches utilizing RNA expression analyses and immunohistochemical studies targeting markers of vascular inflammation and injury. These studies will overlap with studies in Project 2 looking at markers of lung disease and studies in aim 3 looking at vascular inflammation and stress. Biomarkers of disease activity and progression might supplement or, in early phase trials, replace clinical outcome measures, such as the MRSS, potentially permitting short (open label) trials where the skin score would not normally be expected to change significantly. Notably, the potent profibrotic cytokine, transforming growth factor-? (TGF?) regulates two of the genes in our 4-gene skin biomarker (COMP and THS1). We propose in aim 2 to standardize and validate the performance of this 4-gene biomarker of skin disease, by comparing reproducibility in biopsies repeated in adjacent and contralateral forearm, and by examining the change over short and longer periods of time. Finally, in the third aim we propose a short-term open label trial of the high affinity pan-anti-TGF? antibody, GC1008. We will test the hypothesize that this antibody will rapidly inhibit TGF? signature mRNA expression in the 4-gene biomarker, validating utility of the biomarker and providing preliminary proof-of-concept data for a larger clinical trial using this agent.
Systemic sclerosis is a rare scarring disease affecting skin and internal organs frequently leading to death from lung, intestinal or kidney involvement. In this proposal we will identify markers in the blood to better define which patients will progress to have severe complicaitons. We will also carry out a small clinical trial, testing a medication that blocks the most potent regulator in the body of fibrosis (scarring).
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|Fleury, Michelle; Belkina, Anna C; Proctor, Elizabeth A et al. (2018) Increased Expression and Modulated Regulatory Activity of Coinhibitory Receptors PD-1, TIGIT, and TIM-3 in Lymphocytes From Patients With Systemic Sclerosis. Arthritis Rheumatol 70:566-577|
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|Stifano, Giuseppina; Sornasse, Thierry; Rice, Lisa M et al. (2018) Skin Gene Expression Is Prognostic for the Trajectory of Skin Disease in Patients With Diffuse Cutaneous Systemic Sclerosis. Arthritis Rheumatol 70:912-919|
|Franks, Jennifer M; Cai, Guoshuai; Whitfield, Michael L (2018) Feature specific quantile normalization enables cross-platform classification of molecular subtypes using gene expression data. Bioinformatics 34:1868-1874|
|Goswami, Rishov; Cohen, Jonathan; Sharma, Shweta et al. (2017) TRPV4 ION Channel Is Associated with Scleroderma. J Invest Dermatol 137:962-965|
|Cheong, Fei-Ying; Gower, Adam C; Farber, Harrison W (2017) Changes in gene expression profiles in patients with pulmonary arterial hypertension associated with scleroderma treated with tadalafil. Semin Arthritis Rheum 46:465-472|
|Yamashita, Takashi; Asano, Yoshihide; Taniguchi, Takashi et al. (2017) Glycyrrhizin Ameliorates Fibrosis, Vasculopathy, and Inflammation in Animal Models of Systemic Sclerosis. J Invest Dermatol 137:631-640|
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