DDAH As a Novel Target in Pulmonary Fibrosis

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DESCRIPTION (provided by applicant): Candidate: I am an underrepresented scientist proposing an area of research that is of primary interest to the NHLBI (pulmonary research). My keen interest in pulmonary diseases research stems from having lived in an area where chronic lung-related diseases (such as tuberculosis; active- and secondhand- tobacco-smoke as well as wood- and charcoal- smoke related ailments) are endemic due to the poor socio-economic status of the people. As such, I am currently supported by the Tobacco-related Disease Research Program (TRDRP) of the University of California to pursue an important research in this area. During this fellowship, I worked on a project that aimed to conduct high throughput screen (HTS) of small molecules to modify the enzymatic activity of dimethylarginine dimethylaminohydrolase (DDAH); an enzyme involved in cardiovascular physiology by modulating the nitric oxide (NO) synthase (NOS) pathway. I worked diligently with my mentor, Dr Cooke, to design an approach for large-scale production of recombinant DDAH and an assay to conduct the HTS. As described in our recent publication in the journal of Biomolecular Screening, our strategy bear fruit by discovering several novel small molecules that regulate DDAH enzymatic activity. This was particularly very exciting to me as DDAH has been shown to be principally involved in the progression of pulmonary fibrosis in a murine model of lung injury and was found to be upregulated in lung tissues from idiopathic pulmonary fibrosis (IPF) patients. These two important links: DDAH and its role on IPF, and the discovery of small molecules to regulate DDAH activity, fueled my interest in pursuing the development of a novel therapy to restore lung function. Environment: As described in my proposal, my research is significantly accelerated due to it being conducted at Stanford; a superb research environment with multiple core facilities for pharmacological, molecular and cellular studies. In addition, Stanford nurtures multi-disciplinary collaborations and highly committed to translating basic research into clinically useful therapy. Two examples of such bench-to-bedside translational research programs at Stanford are the SPARK and the Bio-X Research Programs. One of the areas that may benefit from such translational research efforts is IPF. At Stanford, there are groups who are actively working towards understanding the pathobiology of IPF and the development of potential therapeutics. One of these groups is my co-mentor, Dr Rosen's, lab that is working on a different target to treat IPF. Their expertise in this area will be valuable i my project. Furthermore, Stanford offers several relevant courses and seminars including Cardiopulmonary Research-in-Progress; Drug Development, and Future Faculty which are of great interest for my career development. Research: IPF is an aggressive and incurable disease that progressively destroys the normal architecture of the lung. Although, the precise etiology and sequence of events in the development and progression of IPF remains incompletely characterized, emerging data indicates that dysregulation of DDAH activity might play crucial role in the pathogenesis of this disease. Recent mechanistic study in an animal model of bleomycin- induced IPF-like lung injury, validated by lung tissues from IPF patients, indicates that DDAH is centrally involved in the disease process. Remarkably, treatment of bleomycin-challenged mice with DDAH inhibitor (L- 291) ameliorated fibrosis and restored lung function. Moreover, analyses of human lung tissue showed that DDAH was significantly elevated in IPF. Therefore, targeting this pathway might have some therapeutic potential as described in my research proposal. One way of regulating DDAH over-activation is by using small molecule antagonists that directly inhibit its enzymatic activity. Therefore, our discovery and validation o several small molecule antagonists of DDAH (including FDA approved ones (for other indication)), deserves further investigation for therapeutic development. Career goals: Practically, drug development is a lengthy process (12 years on average) that requires fundamental understanding of disease mechanisms and optimization of drug-leads to selectively and efficiently target the disease of interest. Therefore, my immediate-term goal is to study the feasibility of DDAH as a drug target in IPF using small molecule-based approach. If the outcome of this study is encouraging, I will then aim for my long-term career goals to conduct step-wise optimization of the drug-leads by forming a network of collaborations to synthesize and test several analogs of the most promising compounds and decipher the mechanism by which such drug-leads regulate DDAH activity. I plan to continue the drug discovery and development path with the ultimate goal of conducting clinical trials and developing a therapy for chronic pulmonary diseases in general and IPF in particular. Therefore, this Research Scientist Development Award from NHLBI will provide me an unparalleled opportunity to develop my career in Biomedical Research and bring innovation to the scientific community. The proposed research is in an area of primary interest to the NHLBI and is feasible given Stanford's research environment and the dedication and expertise of all the personnel tapped in this project. (End of Abstract)