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research overview The focus of our program is to understand the “why” and “how” behind neonates developing diseases, with the ultimate goal of preventing or curing this patient population. We begin with disease phenotypes and investigate the pathogenic mechanisms underlying disease evolution to guide the development of novel future therapies. The phenotypes of interest to our program are necrotizing enterocolitis (NEC), Bronchopulmonary dysplasia (BPD), and rare infectious diseases such as Herpes Simplex virus (HSV), Group B Streptococcus (GBS), and SARS-CoV-2. Our program has adopted a “research without boundaries” approach, which integrates classical “basic”, “clinical” and “translational” strategies. We use human genomic studies, rodent disease models, in vitro studies, and bioinformatics to study mechanisms underlying disease pathogenesis, and testing therapeutic options. Our research vision aligns well with the goals of the CMRI to improve the health of children through multi-disciplinary research. The three major areas of our research focus include: Neonatal Diseases Research Program 1. Vascular remodeling and sub-phenotypes in BPD Investigate dysmorphic vascular arborization in the normal and abnormal lung (BPD). Genomic-Phenomic characterization of BPD sub-phenotypes. 2. Deviant host-pathogen crosstalk in NEC & sepsis Determine how genetic loci program deviant host-pathogen interactions underlying NEC and sepsis phenotypes in neonates. 3. Genomic-Phenomic characterization of neonatal disease susceptibility Discover genetic, phenomic, and transcriptomic signatures that underpin susceptibility to GBS, NEC, and HVS in neonates. Pillars of research program: The cornerstones of our program are phenotype-based research, emphasis on innovation and paradigm-shifting ideas, developing precision tools for phenotype characterization and therapeutics, and emphasis on training future generations of researchers. Accomplishments of our program: At a personal level, and as a research team we have had considerable success in terms of research publications, presentations, and awards at national/ international conferences, intramural and extramural NIH funding, and importantly in discovering and advancing science. A comprehensive list of our research achievements at Children’s Mercy Hospital over the last four years is presented in the subsequent pages. Long-term goal: Our long-term goal is to build an internationally renowned program in neonatal/perinatal research by integrating the skill sets of a diverse team of motivated scientists and collaborators. We will use the knowledge obtained through our investigations to develop precision tools for identifying infants at risk of disease and develop novel treatment strategies to prevent disease. These are commiserated with the CMRI and the NIH vision to promote research that advances the practice of personalized medicine. In subsequent sections, we will highlight the major accomplishments of our program. Support from the CMRI is critical for accomplishing our goals and will establish our program as an international center for research excellence in 5-7 years. Major Scientific Discoveries and Programmatic Accomplishments. 2a - Neonatal Lung Injury and Development: We investigate key modulators of lung endothelial/vascular development and lung injury using models relevant to bronchopulmonary dysplasia (BPD), the most common, debilitating lung disease in premature infants. Key discoveries include establishing a model of sepsis-induced lung remodeling, the discovery of the role of delta-like 4 (DLL4) as a novel regulator of lung vascular and epithelial development [front cover (JCI insights) and editorial (JCI)] and unearthing transcriptional regulation of lung endothelial inflammation [FOSL1 and FOXC2;]. Kindly see section 4 under manuscripts published for a reference list. More recently, we have developed, what I believe is one of the first systemic models for studying systemic SARS-CoV2-induced lung injury. 2b - Combining Genomics, Phenomics and Health Outcomes to Sub-classify BPD: We are pursuing exome sequencing to classify BPD sub-phenotypes in collaboration with the genome center [Drs. Pastinen and Dr. Smail]. In partnership with Drs. Manimtim and Akangire (Neonatology), we will use deep phenotyping and functional phenotyping on BPD infants to characterize BPD sub-phenotypes. Reconciling genetic with phenomic data will provide precision tools to characterize a complex disease and aid the development of phenotype-based approaches for BPD treatment. We have completed sequencing >900 preterm infants with and without BPD, making our study the largest exome study in preterm neonates to date. This maintains our leadership role in neonatal genomics. 2c - BPD therapeutics: More recently we have used our deep understanding on neonatal pathophysiology to probe new therapeutic options for BPD. In collaboration with Drs. Donald DeFranco [Professor & Vice Chair for Medical Education, UPMC], an expert in glucocorticoid signaling, and Dr. Paula Nichols [Professor, Associate Dean for Research, UMKC], we are performing basic and clinical studies on ciclesonide, a synthetic glucocorticoid, as a brain-sparing alternative to dexamethasone therapy for BPD. We have also initiated an industry partnership with COVIS Pharmaceuticals. We have just submitted an R21 application to fund a Phase 1 trial of ciclesonide in babies. 2d - Gene-Microbiota Interactions in NEC: Our focus is on understanding how host genetic variation interacts with developing gut microbiome to modulate the risk of necrotizing enterocolitis, a devastating gastrointestinal illness in preterm infants. Key contributions include identifying potential loci that modulate NEC susceptibility including SIGIRR and ATG16L1. Our research has led to a novel hypothesis for NEC i.e., genetic dysregulation of innate immune response underlies NEC pathogenesis. A major discovery identified SIGIRR regulates postnatal gut adaptation in neonatal mice, and loss of function mutations result in hypersensitivity to gut microbiota-induced inflammation [CMGH Front Cover and editorial]. 2e - NEC Genomics: Our lab has led the field of NEC Genomics with several publications. Recently, we have been analyzing the data from the first exome sequencing study in preterm NEC enrolling >900 infants. We hope to identify several loci that portend NEC vulnerability, laying the path for genetic screening to identifying infants at the highest risk of NEC. 2f - NEC therapeutics: Informed by the work of other investigators and our studies showing the efficacy of probiotics in NEC, we have successfully implemented probiotics to prevent NEC in the CMH-ICN in April 2021. This has resulted in a meaningful reduction in NEC in our infants. This reflects a direct bench-to-bedside translation of our work. We are also working on metabolites such as short-chain fatty acids as a bacteria-free preventive option for NEC. 2g - Genetics of rare neonatal infectious disease and undiagnosed lethal diseases: Our program has had a long-standing interest in severe neonatal Herpes Simplex infections and Group B streptococci. Our lab first discovered that severe neonatal HSV may have a genetic basis using a simple exome survey our ongoing work has identified IRF7 as a potential genetic loci for severe, recurrent neonatal HSV [accepted, Journal of Clinical Investigation]. Once this work is published, it is possibly one of the first human phenotypes for IRF7 mutations. Our ability to do functional studies for VUS has allowed us to identify genetic basis for rare, lethal disease, and return this information to parents for counseling. A recent illustration of this functional genomic work was done with colleagues in the genome center [EPHB4 mutation in neonatal hydrops, Pediatrics]. Programmatic accomplishments: The major accomplishment of our program apart from scientific discovery is establishing institutional, national, and international collaborations which have significantly elevated the status of our program, Neonatology, Pediatrics, and the CMRI nationally. This has resulted in bringing new research projects to Neonatology [NANO NICHD study, PI: Dr. Morowitz, UPMC], LEOPARD [multi-center BPD genomics study, PI: Dr. Hamvas, Northwestern University], and industry [partnership with COVIS is pending]. Our dedication to breaking “silos” has resulted in several fruitful collaborations. Some of these major collaborations are highlighted below. CMH collaborations a) CMKC-Neonatology: Dr. Sampath actively collaborates with the clinical bronchopulmonary dysplasia (BPD) program faculty including Drs. Manimtim and Akangire. Mentoring relationships are highlighted in a different section. b) CMKC – Genomics: Dr. Sampath has active collaborations with Drs. Pastinen, Farrow, Smail, Younger, and Grundberg for our rare and common disease genetic discovery program. c) CMKC – Infectious Disease: Dr. Sampath has an active collaboration with Dr. Susana Chavez Bueno. Our focus is on dissecting the host and bacterial factors determining neonatal E.Coli sepsis. d) CMKC – Allergy Immunology: Dr. Sampath has an active collaboration with Dr. Nikita Raje on understanding immunological basis of rare infectious diseases as well as T cell abnormalities and thymic hypoplasia in DeGeorge syndrome. e) CMKC – Dr. Lane’s lab: Dr. Sampath actively collaborates with Dr. Lane’s lab on the role of DLL4 in neonatal brain development/injury and epigenetic regulation of neonatal/perinatal pathology. Local collaborations a) Dr. Shahid Umar*: We have a long-standing collaboration with Dr. Umar to investigate the emerging gut microbiota in the context of NEC and host genetics. b) Dr. Paula Nichols*: We collaborate on the role of glucocorticoids signaling in neonatal lung and brain injury including testing new synthetic glucocorticoids with less brain toxicity. National and International Collaborations a) Genomics collaborations: We have active collaborations with several PI’s in institutions across the country. Prominent among those include Drs. Dagle (Iowa Children’s Hospital), Good (UNC, North Carolina), Patel (Emory, Atlanta), Underwood (UC Davis, California), Berrington (Newcastle, UK) and others. b) Genome-Microbiome Interactions*: We collaborate with Dr. Morowitz (UPMC, Pittsburgh) as part of the NICHD-funded NANO clinical trial and a Pilot March of Dimes Grant. c) New steroid for preventing BPD in premature infants*: We collaborate with Dr. DeFranco (UPMC) to examine the efficacy of ciclesonide, a brain-sparing synthetic glucocorticoid, in preventing neonatal lung injury without causing neuronal and myelination damage. d) Collaborations in lung vascular biology*: We collaborate with Dr. Ramchandran (MCW, Wisconsin) and Dr. Chen (MD Anderson, Texas) in lung biology. Partnership with industry (Pending) a) Ciclesonide clinical trial: We are in advanced negotiations with COVIS Pharmaceuticals to obtain funding to sponsor a pilot clinical trial of ciclesonide in preterm infants. Once the Phase 1 study is completed we plan to initiate a larger RCT.

One or more keywords matched the following items that are connected to Sampath, Venkatesh

Item TypeName
Concept Child Development
Concept Treatment Outcome
Concept Gene Expression Regulation, Developmental
Concept Molecular Targeted Therapy
Academic Article Risk factors for adverse neurodevelopment in extremely low birth weight infants with normal neonatal cranial ultrasound.
Academic Article Altered postnatal lung development in C3H/HeJ mice.
Academic Article Genetic alterations in necrotizing enterocolitis.
Academic Article Prospective Comparison of Enfamil and Similac Liquid Human Milk Fortifier on Clinical Outcomes in Premature Infants.
Academic Article Co-localization of autophagy-related protein p62 with cancer stem cell marker dclk1 may hamper dclk1's elimination during colon cancer development and progression.
Academic Article Stem cell therapy for preventing neonatal diseases in the 21st century: Current understanding and challenges.
Academic Article Extended course of prednisolone in infants with severe bronchopulmonary dysplasia.
Grant Single Immunoglobulin Interleukin-1 Related Receptor and necrotizing enterocolitis in premature infants
Grant Lipopolysaccharide-mediated oxidative stress and pulmonary vascular injury in Bro
Grant Inflammatory Angiogenesis in the Lung
Grant Developmental Immunotoxicity of PAH in premature infants
Academic Article Challenges in diagnosing necrotizing enterocolitis.
Academic Article Respiratory, growth, and survival outcomes of infants with tracheostomy and ventilator dependence.
Academic Article Intestinal Stem Cell Development in the Neonatal Gut: Pathways Regulating Development and Relevance to Necrotizing Enterocolitis.
Academic Article Delta-like 4 is required for pulmonary vascular arborization and alveolarization in the developing lung.
Academic Article Ciclesonide activates glucocorticoid signaling in neonatal rat lung but does not trigger adverse effects in the cortex and cerebellum.
Academic Article EPHB4 Mutation Suppresses PROX1 Expression and Disrupts Lymphatic Development in Neonatal Hydrops.
Grant A Safer Glucocorticoid to Treat Neonatal Lung Injury with Limited Adverse Neurologic Effects
Academic Article Delta like 4 regulates cerebrovascular development and endothelial integrity via DLL4-NOTCH-CLDN5 pathway and is vulnerable to neonatal hyperoxia.

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