Browsing by Author "Krishnan, Venkatesh"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Genome-Wide Mapping and Interrogation of the Nmp4 Antianabolic Bone Axis
    (Oxford University Press, 2015-09) Childress, Paul; Stayrook, Keith R.; Alvarez, Marta B.; Wang, Zhiping; Shao, Yu; Hernandez-Buquer, Selene; Mack, Justin K.; Grese, Zachary R.; He, Yongzheng; Horan, Daniel; Pavalko, Fredrick M.; Warden, Stuart J.; Robling, Alexander G.; Yang, Feng-Chun; Allen, Matthew R.; Krishnan, Venkatesh; Liu, Yunlong; Bidwell, Joseph P.; Department of Anatomy & Cell Biology, IU School of Medicine
    PTH is an osteoanabolic for treating osteoporosis but its potency wanes. Disabling the transcription factor nuclear matrix protein 4 (Nmp4) in healthy, ovary-intact mice enhances bone response to PTH and bone morphogenetic protein 2 and protects from unloading-induced osteopenia. These Nmp4(-/-) mice exhibit expanded bone marrow populations of osteoprogenitors and supporting CD8(+) T cells. To determine whether the Nmp4(-/-) phenotype persists in an osteoporosis model we compared PTH response in ovariectomized (ovx) wild-type (WT) and Nmp4(-/-) mice. To identify potential Nmp4 target genes, we performed bioinformatic/pathway profiling on Nmp4 chromatin immunoprecipitation sequencing (ChIP-seq) data. Mice (12 w) were ovx or sham operated 4 weeks before the initiation of PTH therapy. Skeletal phenotype analysis included microcomputed tomography, histomorphometry, serum profiles, fluorescence-activated cell sorting and the growth/mineralization of cultured WT and Nmp4(-/-) bone marrow mesenchymal stem progenitor cells (MSPCs). ChIP-seq data were derived using MC3T3-E1 preosteoblasts, murine embryonic stem cells, and 2 blood cell lines. Ovx Nmp4(-/-) mice exhibited an improved response to PTH coupled with elevated numbers of osteoprogenitors and CD8(+) T cells, but were not protected from ovx-induced bone loss. Cultured Nmp4(-/-) MSPCs displayed enhanced proliferation and accelerated mineralization. ChIP-seq/gene ontology analyses identified target genes likely under Nmp4 control as enriched for negative regulators of biosynthetic processes. Interrogation of mRNA transcripts in nondifferentiating and osteogenic differentiating WT and Nmp4(-/-) MSPCs was performed on 90 Nmp4 target genes and differentiation markers. These data suggest that Nmp4 suppresses bone anabolism, in part, by regulating IGF-binding protein expression. Changes in Nmp4 status may lead to improvements in osteoprogenitor response to therapeutic cues.
  • Thumbnail Image
    Item
    Mirikizumab-Induced Transcriptome Changes in Ulcerative Colitis Patient Biopsies at Week 12 Are Maintained Through Week 52
    (Wolters Kluwer, 2023-11-01) Johnson, Travis; Steere, Boyd; Zhang, Pengyue; Zang, Yong; Higgs, Richard; Milch, Catherine; Reinisch, Walter; Panés, Julian; Huang, Kun; D’Haens, Geert; Krishnan, Venkatesh; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public Health
    Introduction: Mirikizumab, an anti-interleukin-23p19 monoclonal antibody, demonstrated efficacy in phase 2 and 3 randomized clinical trials of patients with moderate-to-severe ulcerative colitis (UC). Previous results have shown that 12 weeks of mirikizumab treatment downregulated transcripts associated with UC disease activity and tumor necrosis factor inhibitor resistance. We assessed week-52 gene expression from week-12 responders receiving mirikizumab or placebo. Methods: In the phase 2 AMAC study (NCT02589665), mirikizumab-treated patients achieving week-12 clinical response were rerandomized to mirikizumab 200 mg subcutaneous every 4 or 12 weeks through week 52 (N = 31). Week-12 placebo responders continued placebo through week 52 (N = 7). The limma R package clustered transcript changes in colonic mucosa biopsies from baseline to week 12 into differentially expressed genes (DEGs). Among DEGs, similarly expressed genes (DEGSEGs) maintaining week-12 expression through week 52 were identified. Results: Of 89 DEGSEGs, 63 (70.8%) were present only in mirikizumab induction responders, 5 (5.6%) in placebo responders, and 21 (23.6%) in both. Week-12 magnitudes and week-52 consistency of transcript changes were greater in mirikizumab than in placebo responders (log2FC > 1). DEGSEG clusters (from 84 DEGSEGs identified in mirikizumab and mirikizumab/placebo responders) correlated to modified Mayo score (26/84 with Pearson correlation coefficient [PCC] >0.5) and Robarts Histopathology Index (55/84 with PCC >0.5), sustained through week 52. Discussion: Mirikizumab responders had broader, more sustained transcriptional changes of greater magnitudes at week 52 vs placebo. Mirikizumab responder DEGSEGs suggest a distinct molecular healing pathway associated with mirikizumab interleukin-23 inhibition. The cluster's correlation with disease activity illustrates relationships between clinical, endoscopic, and molecular healing in UC.