Sherine Elsawa, Ph.D.
The transcription factor GLI3 was initially identified as a member of the hedgehog (HH) signaling pathway which plays a role in embryonic development. Later studies showed a role for HH/GLI proteins in several cancers. Additional studies identified other signaling pathways as regulators of GLI proteins leading to different (HH-independent) biological functions. We have shown a novel role for GLI3 in regulating TLRinduced inflammation. While in response to HH signaling GLI3 acts as a transcriptional repressor, in response to TLR signaling, GLI3 acts as a transcriptional activator where it is required for inflammatory cytokine and chemokine expression and secretion in macrophages. Our long-term goal is to understand the role of GLI proteins in immunity. In the proposed research, we will characterize the role of GLI3 in regulating the differentiation of CD4+ T-helper (Th) cell subsets and subsequently its biological function.
We propose to 1) Define the mechanism by which GLI3 modulates IFN飦 and IL-17a production, and 2) Define the biological role of the GLI3 in Th1-mediated anti-tumor immunity and Th17-mediated autoimmunity. The proposed work will provide novel insights into novel role of GLI3 in Th17 cell differentiation and effector functions in disease pathology. These studies will increase our understanding of the role of GLI3 in T cell immunity and enhance our understanding of HH-independent functions of GLI3.
The transcription factor GLI3 modulates the differentiation and effector function of macrophages. It鈥檚 role in adult hematopoiesis and immune function is not well defined. Our investigations represent a defined strategy to enhance our understanding of the molecular mechanisms by which GLI3 modulates CD4+ Th1 and Th17 responses and effector functions serving as a foundation for new therapeutic approaches to regulate CD4+ Th-cell mediated immune disorders.
