A Path to Implement Precision Child Health Cardiovascular Medicine.

Congenital heart defects (CHDs) affect approximately 1% of live births and are a major source of childhood morbidity and mortality even in countries with advanced healthcare systems. Along with phenotypic heterogeneity, the underlying etiology of CHDs is multifactorial, involving genetic, epigenetic, and/or environmental contributors. Clear dissection of the underlying mechanism is a powerful step to establish individualized therapies. However, the majority of CHDs are yet to be clearly diagnosed for the underlying genetic and environmental factors, and even less with effective therapies. Although the survival rate for CHDs is steadily improving, there is still a significant unmet need for refining diagnostic precision and establishing targeted therapies to optimize life quality and to minimize future complications. In particular, proper identification of disease associated genetic variants in humans has been challenging, and this greatly impedes our ability to delineate gene-environment interactions that contribute to the pathogenesis of CHDs. Implementing a systematic multileveled approach can establish a continuum from phenotypic characterization in the clinic to molecular dissection using combined next-generation sequencing platforms and validation studies in suitable models at the bench. Key elements necessary to advance the field are: first, proper delineation of the phenotypic spectrum of CHDs; second, defining the molecular genotype/phenotype by combining whole-exome sequencing and transcriptome analysis; third, integration of phenotypic, genotypic, and molecular datasets to identify molecular network contributing to CHDs; fourth, generation of relevant disease models and multileveled experimental investigations. In order to achieve all these goals, access to high-quality biological specimens from well-defined patient cohorts is a crucial step. Therefore, establishing a CHD BioCore is an essential infrastructure and a critical step on the path toward precision child health cardiovascular medicine

Transcriptome Complexity of Neonatal Heart during Perinatal Circulatory Transition: -- a Road Map for Functional Discovery

During fetal to neonatal circulatory transition, the mammalian heart undergoes an elaborate maturation process involving structural, morphological, and hemodynamic changes that ultimately lead to functional maturation of left and right ventricular chambers as they synchronize to support the systemic and the pulmonary circuits respectively. Perturbation of this process may have major implications in congenital heart defects (CHDs) and pediatric heart diseases. Transcriptome programming is the driving force of cardiac development and pathological remodeling in heart. Although recent progress of deep RNA sequencing technology has revealed much of the landscape of transcriptome regulation in cardiac development and diseases, transcriptome changes during chamber specific maturation or remodeling in neonatal heart in health and disease conditions remain understudied.During the past three years we have made systematic multidisciplinary efforts to address this critical gap of knowledge. We implemented deep RNA-sequencing to establish genome wide transcriptome profiles at single exon resolution in newborn mouse heart during maturation. Our studies reveal that transcriptome maturation during perinatal circulatory transition is a highly dynamic process which is precisely regulated in spatial and temporal manners, affecting transcriptional regulation, molecular signaling, the long noncoding RNAs (lncRNAs) and alternative RNA splicing. Some of these regulatory mechanisms may have potential implications in cardiac maturation, stress response, and neonatal heart diseases. The data provide a comprehensive spatial and temporal landscape of lncRNAs in neonatal heart, revealing their tight regulation and putative function. Among them, several cardiac specific lncRNAs are significantly conserved in human infantile hearts, providing the basis for future investigations in neonatal heart maturation and pathology. Moreover, we discovered chamber specific regulation of Wnt signaling and cellular proliferation programs. From functional studies, we establish for the first time a previously unrecognized significant role of Wnt11 signaling in neonatal heart growth and maturation. More remarkably, we establish that altered regulation of Wnt-mediated signaling in heart of infants with cyanotic CHDs comparing to noncyanotic CHDs, suggesting a potential contribution of Wnt signaling in heart response to chronic hypoxemia. Discovering the functional role of Wnt signaling and exploring the translational implication in early postnatal heart maturation and diseases by establishing the CHD Bio Core at UCLA represent major components of my thesis project

Fetal Mouse Cardiovascular Imaging Using a High-frequency Ultrasound (30/45MHZ) System.

Congenital heart defects (CHDs) are the most common cause of childhood morbidity and early mortality. Prenatal detection of the underlying molecular mechanisms of CHDs is crucial for inventing new preventive and therapeutic strategies. Mutant mouse models are powerful tools to discover new mechanisms and environmental stress modifiers that drive cardiac development and their potential alteration in CHDs. However, efforts to establish the causality of these putative contributors have been limited to histological and molecular studies in non-survival animal experiments, in which monitoring the key physiological and hemodynamic parameters is often absent. Live imaging technology has become an essential tool to establish the etiology of CHDs. In particular, ultrasound imaging can be used prenatally without surgically exposing the fetuses, allowing maintaining their baseline physiology while monitoring the impact of environmental stress on the hemodynamic and structural aspects of cardiac chamber development. Herein, we use the High-Frequency Ultrasound (30/45) system to examine the cardiovascular system in fetal mice at E18.5 in utero at the baseline and in response to prenatal hypoxia exposure. We demonstrate the feasibility of the system to measure cardiac chamber size, morphology, ventricular function, fetal heart rate, and umbilical artery flow indices, and their alterations in fetal mice exposed to systemic chronic hypoxia in utero in real time

COVID-19: molecular diagnostics overview.

The last day of 2019 delivered the first report to the World Health Organization (WHO) about a group of cases of pneumonia of unknown etiology in Wuhan, China. Subsequent investigations identified the new comer, a novel coronavirus related to severe acute respiratory syndrome coronavirus (SARS-CoV) and thus was termed as SARS-CoV-2. Being very contagious, the new virus led the era of "COVID-19" which is the acronym of "coronavirus disease 2019," evoking an imminent threat to global health security with unprecedented devastating challenges to human kind. In this article, we provide a molecular overview on the SARS-CoV-2 virus and summarize tremendous efforts that have been made to develop a rapid confirmatory diagnostic test for COVID-19. The diagnostic performances of the available tests are analyzed based on the best current information from the early research

COVID-19: molecular diagnostics overview.

The last day of 2019 delivered the first report to the World Health Organization (WHO) about a group of cases of pneumonia of unknown etiology in Wuhan, China. Subsequent investigations identified the new comer, a novel coronavirus related to severe acute respiratory syndrome coronavirus (SARS-CoV) and thus was termed as SARS-CoV-2. Being very contagious, the new virus led the era of "COVID-19" which is the acronym of "coronavirus disease 2019," evoking an imminent threat to global health security with unprecedented devastating challenges to human kind. In this article, we provide a molecular overview on the SARS-CoV-2 virus and summarize tremendous efforts that have been made to develop a rapid confirmatory diagnostic test for COVID-19. The diagnostic performances of the available tests are analyzed based on the best current information from the early research