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Sampath, Venkatesh
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research overview
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The focus in the lab is to understand the why and the how behind neonates developing diseases, with the goal of preventing/curing them. The lab starts with disease phenotypes and study the pathogenic mechanisms underlying disease evolution to guide the development of novel future therapies. The phenotypes of interest are necrotizing enterocolitis (NEC), bronchopulmonary dysplasia (BPD), and rare infectious diseases such as herpes simplex virus (HSV) and Group B Streptococcus (GBS). The major challenge is that diseases in neonates and premature infants occupy a unique niche, wherein, injury to the host caused by noxious stimuli such as oxygen toxicity and bacteria occur during critical ontogenic windows. Therefore, disease pathogenesis needs to be examined in the context of developmental processes to decipher mechanism and test potential therapy. The lab uses human genomic studies, rodent pre-clinical models, cell culture studies, and bioinformatics to investigate the mechanisms and sub-phenotype neonatal diseases. The long-term goal is to build an internationally renowned program in neonatal research by integrating the skill sets of a diverse team of motivated scientists and collaborators. The lab uses knowledge obtained through the investigations to develop precision tools for identifying infants at risk of disease and develop novel treatment strategies to prevent or cure disease. The three major areas of research interest are:
I. Lung and BPD Research: Bronchopulmonary dysplasia (BPD) is a debilitating chronic lung disease in premature infants. An area of emphasis is understanding the role of lung endothelial cell (EC) injury/reprogramming in impaired lung and vascular development in BPD. To address this issue, the lab has developed new pre-clinical models of disease, and several transgenic lines to identify the key molecular players that regulate normal and abnormal vascular development. A second challenge is the inability to discern BPD sub-phenotypes, at a genomic and functional level. The lab is addressing this challenge by performing genetic and deep phenotypic characterization in BPD infants.
II. Necrotizing Enterocolitis Research: Necrotizing enterocolitis is a major cause of mortality in premature infants, and represents phenotypes for deviant host-microbiome interactions in the gut. The lab uses forward- and reverse genetics, microbiota studies, and host-bacteria interaction studies to investigate NEC. The immediate focus of this research is the gene, Single Immunoglobulin Interleukin-1 Related Receptor (SIGIRR), which the lab identified as a putative locus for NEC susceptibility. Using novel transgenic mice that encode a NEC-associated genetic mutation the lab discovered and the lab investigated the pathogenesis of NEC. They are also testing several therapies in the pre-clinical and in vivo models.
III. Genetic Basis of Neonatal Disease Susceptibility: The team is one of the leaders in the field of neonatal genomics. The team used low throughput-based single gene or pathway approaches, and are initiating high throughput genome-wide approaches. Apart from complex phenotypes such as BPD and NEC, they are vested in unraveling the genetic basis of rare infectious disease phenotypes such as herpes simplex virus (HSV) and Group B Streptococcus (GBS). They are also initiating deep phenotyping and transcriptome analysis for complex phenotypes, which in combination with genetics, will help sub-classify complex phenotypes. These combined approaches can spur discovery approaches based on mechanism, as well as outcomes research based on interventions.
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Sampath, Venkatesh