DDAH As a Novel Target in Pulmonary Fibrosis

DDAH 作为肺纤维化的新靶点

• 批准号: 9242794
• 负责人: Yohannes T Ghebre
• 金额: $ 14.38万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-30 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9242794
• 关键词: Aerosols; Alveolar; Animal Model; Animals; Apoptosis; Architecture; Area; Attenuated; Basic Science; Binding; Biological Assay; Biology; Biomedical Research; Bleomycin; Blood specimen; Breathing; California; Cardiopulmonary; Cardiovascular Physiology; Cell Culture Techniques; Cell Proliferation; Cells; Cessation of life; Charcoal; Chemicals; Chronic; Chronic lung disease; Collaborations; Collagen; Communities; Conduct Clinical Trials; Core Facility; Data; Dedications; Deposition; Development; Disease; Drug Formulations; Drug Targeting; Elements; Environment; Enzymes; Epithelial; Epithelial Cell Proliferation; Etiology; Event; FDA approved; Feasibility Studies; Fellowship; Fiber; Fibroblasts; Fibrosis; Fruit; Future Teacher; Goals; Hamman-Rich syndrome; Human; Human Resources; Inflammatory; Intention; Investigation; Journals; Kinetics; Laboratories; Lead; Life; Link; Lung; Lung Compliance; Lung Inflammation; Lung diseases; Measures; Mediator of activation protein; Mentored Research Scientist Development Award; Mentors; Molecular; Mus; National Heart, Lung, and Blood Institute; Nitric Oxide Synthase; Outcome Study; Oxygen; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Physiology; Plasma; Play; Process; Proteins; Proton Pump Inhibitors; Publications; Pulmonary Fibrosis; Pulmonary artery structure; Recombinants; Research; Research Personnel; Research Proposals; Respiration; Respiratory physiology; Role; Safety; Scientist; Seminal; Smoke; Smooth Muscle Myocytes; Socioeconomic Status; Structure; Structure of parenchyma of lung; Surface Plasmon Resonance; Testing; Therapeutic; Tissues; Tobacco; Tobacco smoke; Toxic effect; Transgenic Mice; Translating; Translational Research; Tuberculosis; Type II Epithelial Receptor Cell; Universities; Ursidae Family; Validation; Wood material; Work; abstracting; analog; base; bench to bedside; career; career development; cytokine; design; dimethylargininase; drug development; drug discovery; high throughput screening; improved; in vitro activity; indium-bleomycin; inhibitor/antagonist; innovation; insight; interest; large scale production; lung injury; mouse model; novel; novel therapeutics; programs; pulmonary function; screening; small molecule; stem; therapeutic development

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，提出了一项研究领域，该研究领域是NHLBI的主要兴趣（肺部研究）。我对肺部疾病研究的兴趣源于慢性肺有关疾病（例如结核病；活跃和二手烟草 - 烟草以及与木材和木炭相关的疾病）的生活，这是由于人民的社会经济状况不佳而引起的。因此，我目前得到了加利福尼亚大学与烟草相关的疾病研究计划（TRDRP）的支持，以在该领域进行一项重要的研究。在此研究金期间，我从事一个项目，旨在进行小分子的高吞吐量筛选（HTS），以修改二甲基丁金二甲基氨基氢化酶（DDAH）的酶活性；通过调节一氧化氮（NO）合酶（NOS）途径，参与心血管生理的酶。我与导师Cooke Dr勤奋合作，设计了一种大规模生产重组DDAH的方法，并进行了进行HTS的测定方法。正如我们在《生物分子筛查杂志》上的最新出版物中所描述的那样，我们的策略通过发现了几个调节DDAH酶活性的新型小分子来承担果实。这对我来说尤其令人兴奋，因为DDAH已被证明在肺损伤的鼠模型中主要参与肺纤维化的进展，并且发现在特发性肺纤维化（IPF）患者的肺组织中被上调。这两个重要的联系：DDAH及其在IPF中的作用，以及发现调节DDAH活动的小分子的发现，这激发了我对追求新的疗法来恢复肺功能的兴趣。环境：正如我的提案中所述，由于斯坦福大学进行的研究大大加速了。一个精湛的研究环境，具有多个用于药理，分子和细胞研究的核心设施。此外，斯坦福大学培养了多学科的合作，并高度致力于将基础研究转化为临床上有用的疗法。斯坦福大学和BIO-X研究计划是斯坦福大学的基准翻译研究计划的两个例子。 IPF是从这种转化研究工作中受益的领域之一。在斯坦福大学，有些团体正在积极努力理解IPF的病理学和潜在治疗学的发展。这些小组之一是我的联合学者罗森（Rosen）博士实验室，该实验室正在针对治疗IPF的不同目标。我在我的项目中，他们在这方面的专业知识将是有价值的。此外，斯坦福大学提供了几门相关课程和研讨会，包括心肺研究；药物开发和未来的教师，这对我的职业发展引起了极大的兴趣。研究：IPF是一种侵略性且无法治愈的疾病，逐渐破坏了肺部正常建筑。尽管IPF的发展和进展中事件的确切病因和序列仍然没有完全表征，但新兴数据表明DDAH活性的失调可能在该疾病的发病机理中起着至关重要的作用。在IPF患者的肺组织证实的博来霉素诱导的类似IPF的肺损伤的动物模型中，最近的机械研究表明，DDAH集中参与了疾病过程。值得注意的是，用DDAH抑制剂（L-291）对博来霉素挑战的小鼠进行治疗，改善了纤维化并恢复了肺功能。此外，对人肺组织的分析表明，DDAH在IPF中显着升高。因此，针对该途径可能具有一些治疗潜力，如我的研究建议中所述。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，我们的发现和验证o dDAH的几个小分子拮抗剂（包括FDA批准的拮抗剂（用于其他指示）），应该进一步研究治疗性发育。职业目标：实际上，药物开发是一个漫长的过程（平均12年），需要对疾病机制的基本理解和对药物铅的优化，以选择性地有效地针对感兴趣的疾病。因此，我的直接目标是使用基于小分子的方法研究DDAH作为IPF的药物目标的可行性。如果这项研究的结果令人鼓舞，我将通过建立一个合成和测试最有前途的化合物的几个类似物的合作网络来实现我的长期职业目标对药物领导者进行逐步优化，并解解这种药物领导的DDAH活动的机制。我计划继续进行药物发现和开发路径，其最终目的是进行临床试验并尤其是慢性肺部疾病，尤其是IPF的疗法。因此，NHLBI的研究科学家发展奖将为我提供一个无与伦比的机会，可以发展我在生物医学研究领域的职业，并为科学界创新。拟议的研究是NHLBI主要感兴趣的领域，鉴于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是可行的。 （抽象的结尾）