Idiopathic Pulmonary Fibrosis (IPF) is a progressive and ultimately fatal disease in which progressive scarring of the lung destroys their capacity to support necessary gas exchange and function. Genetic predisposition combined with environmental exposure strongly influences the risk of developing IPF. Notably, military personnel have high rates of exposure to potentially harmful inhaled materials, including but not limited to exposure via burn pits, dust storms, industrial emissions and fires, and these exposures increase the risk of chronic and fatal respiratory disorders such as pulmonary fibrosis. Despite the prevalence of IPF (approximately 18 cases per 100,000 in US and approximately 40,000-80,000 deaths annually in US and Europe) and severity of this disease, only two Food and Drug Administration-approved therapies are available (Pirfenidone and Nintedanib), and both show only modest benefits in patient symptoms and quality of life. Importantly, neither drug has been shown to definitively prolong life expectancy or improve lung function. Our published studies show that two proteins, called YAP and TAZ, are found together in lung fibroblasts, a cell type that controls the structure of the lungs. We have found that the continued activities of YAP/TAZ in lung fibroblasts leads to progressive scarring of the lungs in IPF. However, YAP and TAZ are also found in other cell types of the lung and are also important in a number of other key biological processes, which makes it difficult to target them therapeutically to treat just IPF. Therefore, the focus of our proposal is on developing a fibroblast-targeted approach to YAP/TAZ reduction or inhibition. Through preliminary studies, we have identified the dopamine D1 receptor as preferentially found on the surface of lung fibroblasts, but on no other lung resident cell types. Receptors are proteins found on cell surfaces that bind to specific agonists, leading to downstream signaling events. We find that simulation of dopamine receptors leads to inhibition of YAP and TAZ function. The end result of dopamine D1 receptor stimulation is a reversal of fibroblasts from a scar-forming state to one that favors repair and healing of injury. Intriguingly, our preliminary studies also suggest that stimulation of this dopamine receptor and its downstream signals is present in the normal lung but is reduced in the lungs of patients with IPF. This indicates that dopamine signaling may be a normal anti-fibrotic signal that is lost in patients with progressive fibrotic disease. We reason that stimulation of dopamine D1 receptors will be an effective strategy for reversing pulmonary fibrosis by restoring this signal, and thereby switching activated fibroblasts from a fibrosis-promoting to fibrosis-resolving state. However, dopamine D1 receptors are also found in the brain, and most D1 agonist compounds were designed to get into human brains, so we further reason that if we can make new D1 agonist compounds non-brain penetrant, then we can avoid any central nervous system concerns. We propose to test our reasoning in three ways. First, we will design, make, and test new chemical compounds (starting points for drugs) to identify ones that significantly stimulate dopamine D1 receptors but do not enter the brain. This would limit potential neurological side effects. Second, for selected prototype drugs, we will identify the optimal dose and dosing methods to ensure safety and to maximize the desired effects on decreasing YAP/TAZ levels and restoring the fibroblast to a fibrosis-resolving state in the lungs of mice, which is the accepted preclinical model before human studies. Third, we will conclude by evaluating the ability of our new compounds to reverse fibrosis in clinically relevant models of pulmonary fibrosis and compare our new compounds against the currently approved therapies for IPF. By making and testing these new compounds that specifically stimulate the dopamine D1 receptor, confirming their safety and strength, and rigorously confirming their beneficial effects in relevant lung fibrosis models, our work will establish the ability of this new approach to target YAP/TAZ to reverse fibroblast activation and, therefore, reverse progressive pulmonary fibrosis. If successful, this work will set the stage for further development and optimization of a new treatment for IPF and other fibrotic conditions and move the program toward clinical testing in human populations.
|Effective start/end date||1/1/18 → …|
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