Novel pathways of fibrosis: targeting cyclin-dependent kinase

Systemic sclerosis (SSc or scleroderma) is a progressive fibrotic disease with no effective treatment. Impaired function of the peroxisome proliferator activated receptor-gamma (PPAR-gamma)/adiponectin system is associated with fibrosis in SSc, and may represent a fundamental abnormality responsible for fibroblast activation. In light of the novel regulatory function of atypical cyclin dependent kinase CDK5 on PPAR-gamma/adiponectin axis, we propose a critical role for CDK5 in TGF-beta-induced profibrotic responses. I propose to study the regulation and function of CDK5 signaling in pathogenesis of fibrosis in SSc. I will examine how CDK5 activation is regulated in fibroblasts, and whether activated CDK5 signaling in lesional skin identifies a subset of scleroderma patients that might respond to anti-CDK5 therapies. These studies benefit from the resources of the Northwestern Scleroderma Program (including an extensive SSc patient registry and annotated biorepository). In Specific Aim 1, I will use normal skin fibroblasts to investigate the regulation of CDK5 activation and the role of the fibrogenic transcriptional factor Egr-1, and assess CDK5 activation in skin biopsies from well-defined patient cohorts with systemic sclerosis. In Specific Aim 2, I will evaluate the role of CDK5 in experimental mouse fibrosis models by genetic targeting and pharmacological inhibition. If successful, the results will not only provide critical insights regarding novel CDK5 function in fibrogenesis, but also provide proof-of-concept that modulating CDK5 activation might have therapeutic potential in systemic sclerosis.