DDAH As a Novel Target in Pulmonary Fibrosis

DDAH 作为肺纤维化的新靶点

• 批准号: 8789044
• 负责人: Yohannes T Ghebre
• 金额: $ 13.16万
• 依托单位: METHODIST HOSPITAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789044
• 关键词: DDAH; Novel; Target; Pulmonary; Fibrosis

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)

描述（由申请人提供）： 候选人：我是一位代表性不足的科学家，提出了 NHLBI（肺部研究）主要感兴趣的研究领域。我对肺部疾病研究的浓厚兴趣源于我生活在一个慢性肺部相关疾病（例如结核病、活性烟草和二手烟以及木烟和木炭烟相关疾病）流行的地区，因为人民社会经济地位较差。因此，我目前得到加州大学烟草相关疾病研究计划（TRDRP）的支持，在该领域开展重要研究。在这个奖学金期间，我参与了一个项目，旨在对小分子进行高通量筛选（HTS），以修改二甲基精氨酸二甲氨基水解酶（DDAH）的酶活性；一种通过调节一氧化氮 (NO) 合酶 (NOS) 途径参与心血管生理学的酶。我与我的导师 Cooke 博士一起努力工作，设计了一种大规模生产重组 DDAH 的方法以及进行 HTS 的检测方法。正如我们最近在《生物分子筛选》杂志上发表的文章所述，我们的策略通过发现几种调节 DDAH 酶活性的新型小分子而取得了成果。这对我来说尤其令人兴奋，因为在小鼠肺损伤模型中，DDAH 已被证明主要参与肺纤维化的进展，并且发现在特发性肺纤维化 (IPF) 患者的肺组织中表达上调。这两个重要的环节：DDAH 及其对 IPF 的作用，以及调节 DDAH 活性的小分子的发现，激发了我追求开发一种恢复肺功能的新疗法的兴趣。环境：正如我的提案中所述，由于在斯坦福大学进行，我的研究速度显着加快；一流的研究环境，拥有用于药理学、分子和细胞研究的多个核心设施。此外，斯坦福大学还培育多学科合作，并高度致力于将基础研究转化为临床有用的疗法。斯坦福大学此类从实验室到临床的转化研究项目的两个例子是 SPARK 和 Bio-X 研究项目。 IPF 是可能受益于此类转化研究工作的领域之一。在斯坦福大学，有一些小组正在积极致力于了解 IPF 的病理学和潜在治疗方法的开发。其中一个小组是我的共同导师 Rosen 博士的实验室，该实验室正在研究治疗 IPF 的不同目标。他们在该领域的专业知识对于我的项目非常有价值。此外，斯坦福大学还提供多种相关课程和研讨会，包括心肺研究进展；药物开发和未来教师对我的职业发展非常感兴趣。研究：IPF 是一种侵袭性且无法治愈的疾病，会逐渐破坏肺部的正常结构。尽管 IPF 发生和进展的确切病因和事件顺序尚未完全确定，但新出现的数据表明 DDAH 活性失调可能在该疾病的发病机制中发挥至关重要的作用。最近在博莱霉素诱导的 IPF 样肺损伤动物模型中进行的机制研究经 IPF 患者肺组织验证，表明 DDAH 在疾病过程中发挥着重要作用。值得注意的是，用DDAH抑制剂(L-291)治疗博莱霉素攻击的小鼠可改善纤维化并恢复肺功能。此外，对人体肺组织的分析表明，IPF 中 DDAH 显着升高。因此，如我的研究提案中所述，针对该途径可能具有一定的治疗潜力。调节 DDAH 过度激活的一种方法是使用直接抑制其酶活性的小分子拮抗剂。因此，我们对几种 DDAH 小分子拮抗剂（包括 FDA 批准的（用于其他适应症））的发现和验证值得进一步研究以用于治疗开发。职业目标：实际上，药物开发是一个漫长的过程（平均 12 年），需要对疾病机制有基本的了解并优化药物先导物，以选择性和有效地针对感兴趣的疾病。因此，我的近期目标是使用基于小分子的方法研究 DDAH 作为 IPF 药物靶点的可行性。如果这项研究的结果令人鼓舞，那么我将瞄准我的长期职业目标，通过形成合作网络来合成和测试最有前途的化合物的几种类似物并破译，对先导药物进行逐步优化。这些先导药物调节 DDAH 活性的机制。我计划继续药物发现和开发之路，最终目标是进行临床试验并开发针对一般慢性肺部疾病，特别是 IPF 的治疗方法。因此，NHLBI 颁发的研究科学家发展奖将为我提供无与伦比的机会，以发展我在生物医学研究领域的职业生涯，并为科学界带来创新。拟议的研究属于 NHLBI 主要感兴趣的领域，并且考虑到斯坦福大学的研究环境以及该项目中所有人员的奉献精神和专业知识，该研究是可行的。 （摘要完）