Genomic determinants of bronchopulmonary dysplasia development in humans and an animal model

项目总结。 这个以患者为导向的导师研究职业发展奖(K23)的目的是为Alvaro提供 莫雷拉，医学博士，圣安东尼奥德克萨斯大学健康科学中心助理教授， 发展成为独立的学术内科科学家所需的知识和技能。他长期的职业生涯 目的是了解与支气管肺发育相关的病理过程。 发育不良(BPD)是早产儿的一种高发病率和高死亡率的疾病。为此，莫雷拉博士 结合使用高保真技术验证他和他的两个基因组签名(n=20个基因) 指导团队已确定为BPD易感性的强烈预测因子。为了实现这一目标，莫雷拉博士和 他的指导团队已经制定了一个全面的计划，其基础是：(1)深入实践基因组学培训 和生物信息学；(2)高级免疫学的教学和经验指导；(3)严格的培训 临床试验。这个平台将为莫雷拉博士获得技能、知识和经验提供基础 需要制定和测试精辟的假设，以支持新生儿肺部疾病的进展。新生儿 被诊断为BPD的人患全身性(失明、智力缺陷)和特定部位的风险更高 并发症(哮喘、反复呼吸道感染、肺动脉高压)。BPD的特征是 慢性暴露于高氧和呼吸机诱导的损伤后继发的肺发育异常。尽管 在新生儿医学方面的进展，目前的治疗方法有限，而且很大程度上无效。因此，有一种紧迫性。 采取新的策略来缓解和预防BPD。在对潜在机制的理解上存在重大差距 在BPD中，归因于可操作定义、缺乏强大的新生儿组织生物储存库和动物 不能概括人类生理学的错综复杂的模型。翻译基因组学具有重要意义 承诺是克服这些障碍的一种方法。事实上，在一个由120名早产儿组成的发现队列中，Dr。 莫雷拉和他的指导团队已经确定了预测BPD和分层BPD的基因组签名 新生儿出生后头5天的内型。在这项修订后的申请中，莫雷拉博士计划验证两个基因组 一个大的预期早产儿队列中的签名(1，2岁)。在第三年，他将测试一名 根据他的签名定制基因组阵列，以提供快速可靠的BPD风险分层。 此外，莫雷拉博士的研究将评估FDA批准的一种生物制剂的安全性和有效性 一种模仿BPD的大型动物模型。这种单抗针对的是一种可修改的过程，发现 在他来自发现队列的基因组档案中，他对BPD有很高的预测性。莫雷拉博士的K23研究将产生 丰富的学习和教育框架直接为他未来旨在初级预防的R01提案提供信息 BPD的战略。

PROJECT SUMMARY . The purpose of this Mentored Patient-Oriented Research Career Development Award (K23) is to provide Alvaro Moreira, MD, MSc, Assistant Professor at the University of Texas Health Science Center at San Antonio with the knowledge and skills requisite to develop into an independent academic physician scientist. His long-term career goal is to understand the pathologic processes that correlate with the development of bronchopulmonary dysplasia (BPD), a disease with high morbidity and mortality in premature neonates. To this avail, Dr. Moreira is incorporating the use of high-fidelity technology to validate two genomic signatures (n=20 genes) that he and his mentoring team have identified as strong predictors for BPD susceptibility. To achieve this goal, Dr. Moreira and his mentoring team have devised a comprehensive plan based on: (1) an in-depth hands on training in genomics and bioinformatics; (2) didactic and experiential instruction in advanced immunology, and (3) rigorous training in clinical trials. This platform will provide the basis for Dr. Moreira to gain the skills, knowledge and experience needed to formulate and test incisive hypotheses that will bolster advances in neonatal lung disease. Neonates diagnosed with BPD are at increased risk for systemic (blindness, mental deficiency) and site-specific complications (asthma, recurrent respiratory infections, pulmonary hypertension). BPD is characterized by an aberrant lung development secondary to chronic exposure to hyperoxia and ventilator-induced injury. Despite advances in neonatal medicine, current therapies are limited and largely ineffective. Thus, there is an urgency to adopt novel tactics to mitigate and prevent BPD. Significant gaps in understanding the underlying mechanisms in BPD are attributed to an operational definition, a lack of robust neonatal tissue biorepositories, and animal models that do not recapitulate the intricacies of human physiology. Translational genomics holds significant promise as an approach to overcome these barriers. Indeed, in a discovery cohort of 120 preterm neonates, Dr. Moreira and his mentoring team have identified genomic signatures that predict BPD and stratifies BPD endotypes in a neonate's first 5 days of life. In this revised application Dr. Moreira plans to validate two genomic signatures in a large prospective preterm neonatal cohort (Year 1, 2). In Year 3, he will test the ability of a customized genomic array, based on his signatures, to provide a quick and reliable BPD risk stratification. Furthermore, Dr. Moreira's studies will evaluate the safety and efficacy of an FDA-approved biologic in a one of a kind large animal model mimicking BPD. This monoclonal antibody targets a modifiable process found to be highly predictive for BPD in his genomic profile from the discovery cohort. Dr. Moreira's K23 studies will produce a rich learning and educational framework directly informing his future R01 proposal aimed at primary prevention strategies for BPD.