Research Focus of Kumar’s Lab

1.   Obesity associated metabolic syndrome (MetS) is both a US and a worldwide epidemic and a major burden to healthcare system. Chronic low-grade inflammation (CLGI) is a well-established characteristic of the obese-human condition and conventionally, research has focused on the CLGI of liver and adipose tissue as a driver. Though, the gastrointestinal (GI) mucosa is the first tissue that interacts with dietary components and luminal microbiota both of which are known to regulate obesity, the research on the role of GI-mucosa in obesity associated MetS has been ignored. Recent novel findings from my lab support a key role of Janus kinase 3 (Jak3), a non-receptor tyrosine kinase, in intestinal and systemic CLGI associated obesity and diabetes in both an animal-model and in humans. Overall, the existing literature, our publications, and additional unpublished data indicate that Jak3 regulates; colonic and systemic CLGI, and multiple symptoms of basal- and diet-induced obesity and diabetes including, glucose regulatory phenotype, hyperinsulinemia, and liver steatosis. Although the combined evidence supports an essential role for Jak3 in CLGI, a characteristic precursor for obesity and diabetes, there is a critical need to determine the associated underlying mechanisms. In the absence of such knowledge, the potential to identify intestinal-specific factors regulating obesity and diabetes and develop intestinal-based therapeutic interventions to inhibit CLGI characteristic of diabetes will likely remain limited. The research focus of our lab is to determine tissue-specific roles of Jak3 and associated signaling complexes in CLGI-onset as a precursor of multiple chronic diseases including obesity, diabetes, Alzheimer, and inflammatory bowel disease with specific goals to determine a timely intervention to prevent aforementioned complications.

 

2.   Inflammatory bowel disease (IBD) that includes Crohn’s disease and Ulcerative colitis is a chronic inflammatory condition of gastrointestinal tract. Though the annual death from these diseases are over 50,000.00, the incidences of new cases have been rising to be over 100,000 annually.  The intestinal epithelial wound repair functions (Restitution) are compromised during various intestinal disorders including IBD. The research focus of our lab is to dissect the roles of intestinal epithelial, intestinal immune cells and gut microbiota in mucosal restitution and formation of barrier functions. Our lab was first to report the functions of Jak3 in intestinal epithelial mucosa. Our studies show that in an intestinal epithelial cells IL-2 (a cytokine produced during intestinal inflammation) promotes mucosal wound repair where activated Jak3 forms complex with villin and ShcA in an IL-2 dependent manner. We have also shown that that either inhibition of Jak3 activation or intestinal mucosal tissue-specific knock out of Jak3 results in loss of tyrosine phosphorylation of villin, p52ShcA, and beta-catenin, and a significant decrease in mucosal wound repair. Our hypothesis is that JAK3-mediated signaling plays an essential role in intestinal epithelial restitution and barrier functions during normal physiological condition and during intestinal inflammation. Studies are underway to define the tissue-specific Jak3-mediated signaling pathways that regulate CLGI as a precursor for the development of not only IBD but also associated various complication including neurodegeneration and Alzheimer disease.