Friday, July 26, 2024
7/26/2024
¿ DESCRIPTION (provided by applicant): Radiation-induced lung fibrosis is a common consequence of therapeutic thoracic irradiation, with 5-15% of patients developing significant loss of function, deterioration in the quality of life, and even death. Research into the pathogenesis of radiation-induced lung disease is urgently needed since there are no currently approved therapies. The cytokine TGFß plays a key role in promoting differentiation of fibroblasts to myofibroblasts and accumulation of resulting scar tissue. We recently published the exciting and novel finding that lung tissues of patients with lung fibrosis had highly elevated levels of lactic acid. We proposed that lactate in the extracellular matrix lowers the local pH, resulting in activation of latent TGFß that promotes fibrosis. We also discovered that the enzyme that produces lactate, lactate dehydrogenase (LDH), is itself upregulated by TGFß, creating a feed-forward loop that could promote and maintain lung fibrosis. Crucially, LDH is also regulated by the transcription factor HIF1a, which is activated following irradiation in lung cells. Thus, radiation could initiate this feed-forward loop via HIF1a mediated upregulation of lactate production, after which the lactate-TGFß-LDH cycle is self-perpetuating. The interplay of TGFß, LDH and HIF1a represents a novel regulatory axis and potential therapeutic target in radiation-induced fibrosis. Our overall hypothesis is that irradiation promotes lung fibrosis by upregulating HIF1a and lactate dehydrogenase, leading to activation of a pro-fibrotic feed-forward loop in which lactate activates latent TGFß, promoting fibrogenesis and further upregulation of lactate production. To test this hypothesis we have designed the following Specific Aims: Specific Aim 1. Investigate the effect of ionizing radiation on lactate metabolism and production that contributes to lung scarring, and evaluate the efficacy of LDH inhibitors as potential therapeutic agents. Specific Aim 2. Determine the effects of radiation exposure on LDH expression in vivo using human samples and a preclinical animal model, determine the mechanisms that regulate irradiation induced LDH expression, and investigate pharmacologic inhibition of LDH activity as a mitigation strategy. These studies will, for the first time, provide the key mechanistic data linking radiation with fibrosis via excess lactic acid production. We will evaluate exhaled lactate as a potential biomarker for disease progression and treatment efficacy, and we will provide critical proof-of concept data using human samples and preclinical animal models for inhibition of LDH as a novel and viable therapeutic target in radiation-induced lung fibrosis and other scarring diseases.
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