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

人类和动物模型支气管肺发育不良发育的基因组决定因素

• 批准号: 10609844
• 负责人: Alvaro G Moreira
• 金额: $ 16.31万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-23 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609844
• 关键词: Address; Adopted; Adrenal Cortex Hormones; Animal Model; Archives; Asthma; Beds; Bioinformatics; Biological; Biological Products; Birth Weight; Blindness; Blood; Blood specimen; Body Weight; Bronchopulmonary Dysplasia; Childhood; Chronic; Clinical; Clinical Research; Clinical Trials; Coughing; Coupled; Custom; Data; Development; Diagnosis; Disease; Double-Blind Method; Education; Exposure to; FDA approved; Future; Gene Expression; Genes; Genomic approach; Genomics; Goals; Health Care Costs; Health Sciences; Hospitalization; Human; Hyperoxia; Immunity; Immunology; Impairment; Inflammation; Injury; Institution; Instruction; Knowledge; Learning; Life; Lung; Lung diseases; Medicine; Mental deficiency; Mentored Patient-Oriented Research Career Development Award; Mentors; Modality; Modeling; Monoclonal Antibodies; Morbidity - disease rate; Mutation; Neonatal; Neonatal Intensive Care Units; Outcome; Papio; Pathologic Processes; Pathway interactions; Patient Care; Patients; Persons; Pharmaceutical Preparations; Physicians; Physiology; Predisposition; Pregnancy; Prevention; Prevention strategy; Preventive; Primary Prevention; Process; Pulmonary Hypertension; Recurrence; Research; Respiratory Tract Infections; Risk; Risk Factors; Safety; Scientist; Secondary to; Severities; Severity of illness; Site; Symptoms; T-Lymphocyte; Technology; Testing; Texas; Time; Tissues; Training; Universities; Validation; Ventilator; Ventilator-induced lung injury; Wheezing; biobank; biomarker discovery; career; clinically significant; cohort; disability; efficacy testing; eosinophil; experience; extreme prematurity; genetic signature; genomic profiles; genomic signature; genomic tools; improved; innovation; lung development; lung injury; mortality; nano-string; neonate; novel; novel strategies; patient oriented; peripheral blood; predictive signature; preterm newborn; prevent; professor; prospective; pulmonary function; randomized, clinical trials; respiratory; risk stratification; skills; surfactant; text searching; therapeutic target; tool; transcriptome sequencing; transcriptomics; translational genomics; whole genome

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.

项目摘要。 这个以患者为导向的研究职业发展奖（K23）的目的是为阿尔瓦罗提供 Moreira，医学博士、理学硕士，德克萨斯大学圣安东尼奥健康科学中心助理教授 发展成为独立学术医师科学家所需的知识和技能。他的长期职业生涯 目标是了解与支气管肺发育相关的病理过程 发育不良（BPD）是一种早产儿发病率和死亡率较高的疾病。为此，莫雷拉博士 结合使用高保真技术来验证他和他的两个基因组特征（n=20 个基因） 指导团队已将其确定为 BPD 易感性的有力预测因素。为了实现这一目标，莫雷拉博士和 他的指导团队根据以下内容制定了全面的计划：（1）深入的基因组学实践培训 和生物信息学； (2) 高级免疫学的教学和体验式指导，以及 (3) 严格的培训 临床试验。该平台将为莫雷拉博士提供获得技能、知识和经验的基础 需要制定和测试尖锐的假设，以促进新生儿肺病的进展。新生儿 被诊断患有 BPD 的系统性（失明、精神缺陷）和特定部位的风险增加 并发症（哮喘、反复呼吸道感染、肺动脉高压）。 BPD 的特点是 慢性暴露于高氧和呼吸机引起的损伤继发的肺部发育异常。尽管 随着新生儿医学的进步，目前的治疗方法有限且基本上无效。因此，当务之急是 采用新颖的策略来减轻和预防 BPD。在理解潜在机制方面存在重大差距 BPD 中的 BPD 归因于操作定义、缺乏强大的新生儿组织生物库以及动物 模型不能概括人类生理学的复杂性。转化基因组学具有重要意义 承诺作为克服这些障碍的一种方法。事实上，在一个由 120 名早产新生儿组成的发现队列中，Dr. Moreira 和他的指导团队已经确定了预测 BPD 并对 BPD 进行分层的基因组特征 新生儿出生后 5 天的内型。在这个修订后的应用程序中，莫雷拉博士计划验证两个基因组 大型前瞻性早产新生儿队列（第一年、第二年）的特征。在第三年，他将测试一个人的能力 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，Moreira 博士的研究将评估 FDA 批准的生物制剂在以下一项中的安全性和有效性： 一种模仿 BPD 的大型动物模型。这种单克隆抗体针对的是一个可修改的过程，该过程被发现是 他的发现队列基因组图谱高度预测了 BPD。 Moreira 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 的策略。