Fibroproliferative disorders are common, progressive and refractory to available therapy. Fibroblasts derived from fibroproliferative lesions manifest an unexplained autonomy for growth and survival signals. In this revised proposal, we propose to study lung fibroblasts from patients with Idiopathic Pulmonary Fibrosis (IPF), a prototype fibroproliferative disease, and elucidate the mechanism of autonomous function using our recent discoveries in cancer biology as a guide. In studies of human breast carcinoma, we discovered that autonomy is conferred by deregulation of the cap-dependent translation initiation machinery, designated eIF4F. In normal cells, eIF4F receives signals from matrix and growth factor receptors and their downstream intermediates, and orchestrates these inputs into a physiological growth response. In cancer cells, eIF4F serves to integrate and amplify diverse growth and survival signals emanating from a plethora of growth-related genes to confer autonomy. Here we show preliminary data indicating that aberrant activation of eIF4F is a property of IPF fibroblasts; that activating eIF4F in fibroblasts stimulates cell cycle entry in the absence of growth factors; and that mice genetically engineered to lack negative regulators of eIF4F have an exaggerated fibrotic response. We therefore hypothesize that deregulated translational control of transcripts governing cell cycle transit lies on the causal pathway to fibrosis; and propose 2 specific aims to test this hypothesis:
Specific Aim 1 : Classify transcripts in IPF fibroblasts that display coordinate changes in translational efficiency into discrete groups based on shared chemical and biological characteristics. A. Chemical: Nucleotide sequences that comprise known or candidate RNA regulatory elements. B. Biological: Assigned function.
Specific Aim 2 : Focusing on transcripts encoding cell cycle regulators, determine whether disrupting regulatory element function attenuates IPF fibroblast proliferative autonomy. A. Known regulatory elements. B. Newly discovered regulatory elements. If successful, our studies will precisely identify derangements in the translational step of gene expression that confer IPF fibroblasts with proliferative autonomy, thus revealing new classes of molecular targets for antifibrotic therapy in the lung and other organs.
. Many human diseases are characterized by scar tissue accumulation that leads to organ dysfunction and death. Scarring, also called fibrosis, can affect many different organs including the lung, liver, kidney, heart, vasculature and skin; and is often very difficult to treat. Here we propose to study the cell producing scar tissue, the fibroblast, in a deadly form of lung scarring that afflicts more than 35,000 people in the US, termed idiopathic pulmonary fibrosis (IPF). Our pilot experiments point to abnormal activation of the cellular machinery that produces protein, in a pattern similar to that seen in cancer. Our goal in this study is to understand how the biology of fibroblasts can be redirected by abnormalities in the protein synthesis machinery in a manner that leads to lung fibrosis. This information has the potential to lead to new treatments for all scarring diseases by revealing new molecular targets for antifibrotic therapy. ? ? ?
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