Browsing by Author "Zhang, Li"

Now showing 1 - 7 of 7
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    Corrigendum: Regulatory T cells targeting a pathogenic MHC class II: insulin peptide epitope postpone spontaneous autoimmune diabetes
    (Frontiers Media, 2024-03-07) Obarorakpor, Nyerhovwo; Patel, Deep; Boyarov, Reni; Amarsaikhan, Nansalmaa; Cepeda, Joseph Ray; Eastes, Doreen; Robertson, Sylvia; Johnson, Travis; Yang, Kai; Tang, Qizhi; Zhang, Li; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    In the published article, there was an error in the Funding statement. Grant “JDRF 2-SRA-2018-648-S-B” grant was missing in the statement. The correct Funding statement appears below. Funding This study was supported by grants from NIH R03AI139811-01A1, DoD W81XWH2210087, JDRF 2-SRA-2018-648-S-B, and a Pilot and Feasibility Award from the CDMD NIH/NIDDK Grant Number P30 DK097512 (to LZ). The authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.
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    Defective osteogenesis of the stromal stem cells predisposes CD18-null mice to osteoporosis
    (2005-09-27) Miura, Yasuo; Miura, Masako; Gronthos, Stan; Allen, Matthew R.; Cao, Chunzhang; Uveges, Thomas E.; Bi, Yanming; Ehirchiou, Driss; Kortesidis, Angela; Shi, Songtao; Zhang, Li
    Osteogenesis by the bone marrow stromal stem cells (BMSSCs) supports continuous bone formation and the homeostasis of the bone marrow microenvironment. The mechanism that controls the proliferation and differentiation of BMSSCs is not fully understood. Here, we report that CD18, a surface protein present primarily on hematopoietic cells, but not on differentiated mesenchymal cells, is expressed by the stromal stem cells and plays a critical role in the osteogenic process. Constitutive expression of CD18 on BMSSCs using a retroviral promoter significantly enhances bone formation in vivo, whereas genetic inactivation of CD18 in mice leads to defective osteogenesis due to decreased expression of the osteogenic master regulator Runx2/Cbfa1. The defective osteogenesis of the CD18-null BMSSCs can be restored by expressing full-length, but not cytoplasmic domain-truncated, CD18. Radiographic analyses with dual-energy x-ray absorptiometry and 3D microcomputed tomography show that mice lacking CD18 have decreased bone mineral density and exhibit certain features of osteoporosis. Altogether, this work demonstrates that CD18 functions critically in the osteogenesis of BMSSCs, and thus lack of CD18 expression in the leukocyte adhesion deficiency patients may predispose them to osteoporosis.
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    Differential integrated stress response and asparagine production drive symbiosis and therapy resistance of pancreatic adenocarcinoma cells
    (Springer Nature, 2022) Halbrook, Christopher J.; Thurston, Galloway; Boyer, Seth; Anaraki, Cecily; Jiménez, Jennifer A.; McCarthy, Amy; Steele, Nina G.; Kerk, Samuel A.; Hong, Hanna S.; Lin, Lin; Law, Fiona V.; Felton, Catherine; Scipioni, Lorenzo; Sajjakulnukit, Peter; Andren, Anthony; Beutel, Alica K.; Singh, Rima; Nelson, Barbara S.; Van Den Bergh, Fran; Krall, Abigail S.; Mullen, Peter J.; Zhang, Li; Batra, Sandeep; Morton, Jennifer P.; Stanger, Ben Z.; Christofk, Heather R.; Digman, Michelle A.; Beard, Daniel A.; Viale, Andrea; Zhang, Ji; Crawford, Howard C.; di Magliano, Marina Pasca; Jorgensen, Claus; Lyssiotis, Costas A.; Pediatrics, School of Medicine
    The pancreatic tumor microenvironment drives deregulated nutrient availability. Accordingly, pancreatic cancer cells require metabolic adaptations to survive and proliferate. Pancreatic cancer subtypes have been characterized by transcriptional and functional differences, with subtypes reported to exist within the same tumor. However, it remains unclear if this diversity extends to metabolic programming. Here, using metabolomic profiling and functional interrogation of metabolic dependencies, we identify two distinct metabolic subclasses among neoplastic populations within individual human and mouse tumors. Furthermore, these populations are poised for metabolic cross-talk, and in examining this, we find an unexpected role for asparagine supporting proliferation during limited respiration. Constitutive GCN2 activation permits ATF4 signaling in one subtype, driving excess asparagine production. Asparagine release provides resistance during impaired respiration, enabling symbiosis. Functionally, availability of exogenous asparagine during limited respiration indirectly supports maintenance of aspartate pools, a rate-limiting biosynthetic precursor. Conversely, depletion of extracellular asparagine with PEG–asparaginase sensitizes tumors to mitochondrial targeting with phenformin.
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    Effective combinatorial immunotherapy for penile squamous cell carcinoma
    (Springer Nature, 2020-05-01) Huang, Tianhe; Cheng, Xi; Chahoud, Jad; Sarhan, Ahmed; Tamboli, Pheroze; Rao, Priya; Guo, Ming; Manyam, Ganiraju; Zhang, Li; Xiang, Yu; Han, Leng; Shang, Xiaoying; Deng, Pingna; Luo, Yanting; Lu, Xuemin; Feng, Shan; Ferrer, Magaly Martinez; Wang, Y. Alan; DePinho, Ronald A.; Pettaway, Curtis A.; Lu, Xin; Medicine, School of Medicine
    Penile squamous cell carcinoma (PSCC) accounts for over 95% of penile malignancies and causes significant mortality and morbidity in developing countries. Molecular mechanisms and therapies of PSCC are understudied, owing to scarcity of laboratory models. Herein, we describe a genetically engineered mouse model of PSCC, by co-deletion of Smad4 and Apc in the androgen-responsive epithelium of the penis. Mouse PSCC fosters an immunosuppressive microenvironment with myeloid-derived suppressor cells (MDSCs) as a dominant population. Preclinical trials in the model demonstrate synergistic efficacy of immune checkpoint blockade with the MDSC-diminishing drugs cabozantinib or celecoxib. A critical clinical problem of PSCC is chemoresistance to cisplatin, which is induced by Pten deficiency on the backdrop of Smad4/Apc co-deletion. Drug screen studies informed by targeted proteomics identify a few potential therapeutic strategies for PSCC. Our studies have established what we believe to be essential resources for studying PSCC biology and developing therapeutic strategies.
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    H19 potentiates let-7 family expression through reducing PTBP1 binding to their precursors in cholestasis
    (Springer Nature, 2019-02-18) Zhang, Li; Yang, Zhihong; Huang, Wendong; Wu, Jianguo; Medicine, School of Medicine
    Cholestasis induces the hepatic long non-coding RNA H19, which promotes the progression of cholestatic liver fibrosis. However, microRNAs that are dysregulated by H19 during cholestasis remain elusive. Using miRNA-sequencing analysis followed by qPCR validation, we identified marked upregulation of eight members of the let-7 family in cholestatic livers by bile duct ligation (BDL) and H19 overexpression. In particular, the expression of let-7a-1/7d/7f-1 was highly induced in H19-BDL livers but decreased in H19KO-BDL livers. Interestingly, H19 decreased the nuclear let-7 precursors as well as the primary transcripts of let-7a-1/7d/7f-1 levels in BDL mouse livers. Bioinformatics, RNA pull-down, and RNA immunoprecipitation (RIP) assays revealed that the crucial RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1), an H19 interaction partner, interacted with the precursors of let-7a-1 and let-7d and suppressed their maturation. Both PTBP1 and let-7 expression was differentially regulated by different bile acid species in hepatocyte and cholangiocyte cells. Further, H19 negatively regulated PTBP1's mRNA and protein levels but did not affect its subcellular distribution in BDL mouse livers. Moreover, we found that H19 restrained but PTBP1 facilitated the bioavailability of let-7 miRNAs to their targets. Taken together, this study revealed for the first time that H19 promoted let-7 expression by decreasing PTBP1's expression level and its binding to the let-7 precursors in cholestasis.
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    OGR1/GPR68 Modulates the Severity of Experimental Autoimmune Encephalomyelitis and Regulates Nitric Oxide Production by Macrophages.
    (PLOS, 2016) D’Souza, Cheryl A.; Zhao, Fei Linda; Li, Xujian; Xu, Yan; Dunn, Shannon E.; Zhang, Li; Department of Obstetrics & Gynecology, IU School of Medicine
    Ovarian cancer G protein-coupled receptor 1 (OGR1) is a proton-sensing molecule that can detect decreases in extracellular pH that occur during inflammation. Although OGR1 has been shown to have pro-inflammatory functions in various diseases, its role in autoimmunity has not been examined. We therefore sought to determine whether OGR1 has a role in the development of T cell autoimmunity by contrasting the development of experimental autoimmune encephalomyelitis between wild type and OGR1-knockout mice. OGR1-knockout mice showed a drastically attenuated clinical course of disease that was associated with a profound reduction in the expansion of myelin oligodendrocyte glycoprotein 35-55-reactive T helper 1 (Th1) and Th17 cells in the periphery and a reduced accumulation of Th1 and Th17 effectors in the central nervous system. We determined that these impaired T cell responses in OGR1-knockout mice associated with a reduced frequency and number of dendritic cells in draining lymph nodes during EAE and a higher production of nitric oxide by macrophages. Our studies suggest that OGR1 plays a key role in regulating T cell responses during autoimmunity.
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    Regulatory T cells targeting a pathogenic MHC class II: Insulin peptide epitope postpone spontaneous autoimmune diabetes
    (Frontiers Media, 2023-08-01) Obarorakpor, Nyerhovwo; Patel, Deep; Boyarov, Reni; Amarsaikhan, Nansalmaa; Cepeda, Joseph Ray; Eastes, Doreen; Robertson, Sylvia; Johnson, Travis; Yang, Kai; Tang, Qizhi; Zhang, Li; Biostatistics and Health Data Science, School of Medicine
    Introduction: In spontaneous type 1 diabetes (T1D) non-obese diabetic (NOD) mice, the insulin B chain peptide 9-23 (B:9-23) can bind to the MHC class II molecule (IAg7) in register 3 (R3), creating a bimolecular IAg7/InsulinB:9-23 register 3 conformational epitope (InsB:R3). Previously, we showed that the InsB:R3-specific chimeric antigen receptor (CAR), constructed using an InsB:R3-monoclonal antibody, could guide CAR-expressing CD8 T cells to migrate to the islets and pancreatic lymph nodes. Regulatory T cells (Tregs) specific for an islet antigen can broadly suppress various pathogenic immune cells in the islets and effectively halt the progression of islet destruction. Therefore, we hypothesized that InsB:R3 specific Tregs would suppress autoimmune reactivity in islets and efficiently protect against T1D. Methods: To test our hypothesis, we produced InsB:R3-Tregs and tested their disease-protective effects in spontaneous T1D NOD.CD28-/- mice. Results: InsB:R3-CAR expressing Tregs secrete IL-10 dominated cytokines upon engagement with InsB:R3 antigens. A single infusion of InsB:R3 Tregs delayed the onset of T1D in 95% of treated mice, with 35% maintaining euglycemia for two healthy lifespans, readily home to the relevant target whereas control Tregs did not. Our data demonstrate that Tregs specific for MHC class II: Insulin peptide epitope (MHCII/Insulin) protect mice against T1D more efficiently than polyclonal Tregs lacking islet antigen specificity, suggesting that the MHC II/insulin-specific Treg approach is a promising immune therapy for safely preventing T1D.