A5050487777- Endoplasmic Reticulum Stress and Disease
- RNA regulation and disease
- Immune Cell Function and Interaction
- Diabetes and associated disorders
- Pancreatic function and diabetes
- T-cell and B-cell Immunology
- RNA Research and Splicing
- Fibroblast Growth Factor Research
- Autophagy in Disease and Therapy
- Heat shock proteins research
- Complement system in diseases
- Liver Disease Diagnosis and Treatment
- Iron Metabolism and Disorders
- Liver Diseases and Immunity
- Kruppel-like factors research
- Advanced Glycation End Products research
- RNA and protein synthesis mechanisms
- RNA modifications and cancer
- Reproductive System and Pregnancy
Cincinnati Children's Hospital Medical Center
2011-2019
Indiana University School of Medicine
2014-2017
Indiana University – Purdue University Indianapolis
2013-2017
Environmental stresses that disrupt protein homeostasis induce phosphorylation of eIF2, triggering repression global synthesis coincident with preferential translation ATF4, a transcriptional activator the integrated stress response (ISR). Depending on extent disruption, ATF4 may not be able to restore proteostatic control and instead switches terminal outcome features elevated expression transcription factor CHOP (GADD153/DDIT3). The focus this study is define mechanisms by which directs...
Disturbances in protein folding and membrane compositions the endoplasmic reticulum (ER) elicit unfolded response (UPR). Each of three UPR sensory proteins-PERK (PEK/EIF2AK3), IRE1, ATF6-is activated by ER stress. PERK phosphorylation eIF2 represses global synthesis, lowering influx nascent polypeptides into stressed ER, coincident with preferential translation ATF4 (CREB2). In cultured cells, induces transcriptional expression genes directed arm UPR, including involved amino acid...
Disruption of protein folding in the endoplasmic reticulum (ER) triggers unfolded response (UPR), a transcriptional and translational control network designed to restore homeostasis. Central UPR is PKR-like ER kinase (PERK/EIF2AK3) phosphorylation α subunit eIF2 (eIF2α∼P), which represses global translation coincident with preferential mRNAs, such as activating transcription factor 4 (ATF4) C/EBP-homologous (CHOP), that serve implement regulation. In this study, we used sucrose gradient...
Complement, NKT, and NK cells play critical roles in the first line defense against pathogens. Functional for both C5a receptors, that is, complement receptor (C5aR) receptor-like 2 (C5L2), sepsis have been demonstrated. However, role of innate lymphocyte activation during remains elusive. In this article, we show naive NKT already express high levels C5aR minor C5L2 mRNA, but no protein. Upon Escherichia coli-induced sepsis, found surface expression on subpopulations cells, suggesting rapid...
The antileukemic agent asparaginase triggers the amino acid response (AAR) in liver by activating eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible (GCN2). To explore mechanism which AAR induction is necessary to mitigate hepatic lipid accumulation and prevent dysfunction during continued treatment, wild-type Gcn2 null mice were injected once daily with or phosphate buffered saline for up 14 days. Asparaginase induced mRNA expression of multiple genes greatly...
Environmental and genetic factors define the susceptibility of an individual to autoimmune disease. Although common pathways affect general immunological tolerance mechanisms in autoimmunity, effects such genes could vary under distinct immune challenges within different tissues. In this study, we demonstrate by observing that type 1 diabetes-protective haplotypes at insulin-dependent diabetes region 10 (Idd10) introgressed from chromosome 3 C57BL/6 (B6) A/J mice onto NOD background increase...
We have previously proposed that sequence variation of the CD101 gene between NOD and C57BL/6 mice accounts for protection from type 1 diabetes (T1D) provided by insulin-dependent susceptibility region 10 (Idd10), a <1 Mb on mouse chromosome 3. In this study, we provide further support hypothesis Cd101 is Idd10 using haplotype expression analyses novel congenic strains coupled to development knockout mouse. Susceptibility T1D was correlated with genotype-dependent multiple cell subsets,...
Type 1 diabetes (T1D) is a chronic multi-factorial disorder characterized by the immune-mediated destruction of insulin-producing pancreatic beta cells. Variations at large number genes influence susceptibility to spontaneous autoimmune T1D in non-obese diabetic (NOD) mice, one most frequently studied animal models for human disease. The genetic analysis these mice allowed identification many insulin-dependent (Idd) loci and candidate genes, them being Cd101. CD101 heavily glycosylated...
Phosphorylation of eIF2 (eIF2‐P) lowers protein synthesis to conserve resources and facilitate preferential translation specific transcripts that promote adaptation environmental stresses. Central the mechanisms are upstream ORFs (uORFs) embedded within 5′‐leaders mRNAs, which serve as “bar codes” help ribosomes determine levels mRNA coding sequences (CDS) during eIF2‐P. We have been studying functions uORFs demarcate translational control roles these preferentially translated genes play in...