Shiv Kumar

Sanford Burnham Prebys Medical Research Institute, LA JOLLA, United States

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My interdisciplinary research unites various fields of genome-wide molecular biology, biochemistry, and proteomics tools. I am always enthusiastic to study the detailed molecular mechanism of duct morphogenesis and regeneration potential targeting ALGS. Our ongoing research is focused on Alagille Syndrome (ALGS) (a haploinsufficient Jagged/Notch disorder) and we are currently investigating the therapeutic potential of an FDA-approved drug NoRA1 (Coded name, an agonist of Notch signaling) to target the AGLS syndrome. The haploinsufficiency of Jag1 causes liver and heart defects, bile duct paucity, jaundice, kidney abnormalities, pancreatic insufficiency, vascular abnormalities, mild developmental delays, congenital impairments, and many others. Our research has shown that the endoderm Notch legends Jag2a and Jag2b is critically required for duct lineage specification in the liver and pancreas in the zebrafish. Our research demonstrated that NoRA1 induces the expression of Duct regeneration and duct differentiation markers, Sox9, Hes1, MDR1 (Bile canaliculi marker), MRP2 (Bile canaliculi marker), and Epcam (cholangiocyte marker) in cells and mice liver tissue. Sox9 and Hes1 are needed for duct regeneration in the liver while MDR1 and MRP2 lead the bile canaliculi to transport the bile from the liver to the gall bladder. Our preliminary results have shown that NoRA1 induces the cleavage of Notch and promotes nuclear localization of NICD fragments in different cell types. DARTS assay showed NoRA1 physically binds within in NRR domain of Notch and stabilized its protein level. Further, NoRA1 increases Sox9 and MDR1 protein levels in HepG2 and HepG2-Jag1+/--derived spheroids. We have developed a double heterozygous Jag1+/-; Notch2+/-mice model. The blood chemistry and immunostaining of Jag1+/-; Notch2+/- mice have shown an augmented level of total bilirubin (TBIL) in plasma and reduced levels of MDR1 in liver histology. Augmented level of TBIL indicates bile duct leakage and liver damage while reduced levels of MDR1 explicit less or no bile duct formation in the liver. This mouse model mimics the ALGS syndrome in humans. Taken together, we propose that NoRA1-induced duct regeneration (Sox9 and Hes1) and bile canaliculi markers (MDR1 and MRP2) can rescue duct loss in a Jag1+/- ; Notch2+/- mice model system and NoRA1 could be a potential therapeutic agent to regenerate the ducts to target ALGS. Moreover, this study helps to evaluate the therapeutic potential of other drugs like molecules and Notch agonists to treat ALGS symptoms and other diseases in humans.

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