The proposal details a comprehensive five years training program to expand my skills as a physician-scientist.
The research plan is focused on JAK-STAT pathway in Celiac Disease (CeD), but the training plan includes
extensive didactics in human subject research, bioinformatics and laboratory-based training on T cell
immunology. CeD is an immune mediated gastrointestinal disease that arises in patients with a permissive
HLA-DQ2/HLA-DQ8 genetic background. The only available treatment for CeD is to follow a gluten-free diet.
Patients with germline gain-of-function (GOF) STAT3 mutations and Down Syndrome have an estimated 40-
fold and 5-fold higher risk of CeD, respectively, than the general population, along with a predisposition for
other autoimmune diseases, including thyroiditis and Type I Diabetes. Patients with Down Syndrome have
three copies of the gene for interferon (IFN) receptors on chromosome 21 and thus constitutive JAK-STAT
activation. The central hypothesis is that interferon and cytokines mediated JAK-STAT overactivation may
cause loss of T cell tolerance to gluten and an increased risk for CeD. The overall goal of this research is to
investigate the mechanism of JAK-STAT activation in the pathogenesis of CeD. To accomplish this, first, we
will conduct genetic investigation in 100 index cases with familial CeD and search for genetic variants in the
JAK-STAT pathway. We will also expand our cohort of CeD patients with known genetic diseases affecting
JAK-STAT activation, include patients with GOF-STAT3 and DS. Second, we will assess the key molecules in
the JAK-STAT pathway, including agonists, receptors, STAT and their phosphorylated forms, ISGs in
monocyte and CD4+ T cells to identify a molecular signature of active CeD. Third, we will investigate the
mechanisms of JAK-STAT overactivation on gluten-specific CD4+ T cells through both single cell RNA-Seq and
amplified T cell libraries, followed by testing the functional impact of JAK inhibitors on gluten-specific T cells.
The results of this study will delineate JAK-STAT activation and its potential as a therapeutic target for Celiac
Disease. Furthermore, through the proposed complementary career development plan, I will gain additional
training in clinical investigation on the genetics and immunology of CeD; advanced bioinformatic analysis with
RNA-seq; and laboratory-based training in gluten specific CD4+ T cells biology. Throughout this research and
career development activities, I will be mentored by a team lead by Dr. Timothy Wang, an internationally
recognized physician-scientist and an expert in inflammatory cytokines and their role in human gastrointestinal
diseases. I am committed to a career as an independent investigator in patient-oriented translational research;
and have designed my training plan to acquire the knowledge and skills needed to make a meaningful and
substantial contribution to the field by using a functional genetics approach to discover the therapeutic targets
in gastrointestinal diseases.