Date of Award
2014
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Biotechnology Science and Engineering
Committee Chair
Joseph D. Ng
Committee Member
Shawn E. Levy
Committee Member
Debra M. Moriarity
Committee Member
Luis R. Cruz-Vera
Committee Member
Devin Absher
Committee Member
Greg Cooper
Subject(s)
Nervous system--Diseases--Genetic aspects, Genetic disorders, Cellular signal transduction, Calcium--Physiological effect, Myotonia atrophica
Abstract
Myotonic dystrophy (DM) is a mutisystemic neurological disorder with an autosomal dominant inheritance involving skeletal and cardiac muscles. There are two different types of DM identified; type1 myotonic dystrophy (DM1) and type2 myotonic dystrophy (DM2). In this study I undertook an intense unbiased investigative approach by profiling the global mRNA, miRNA and protein expression landscape in skeletal muscle biopsies from DM1 and DM2 patients. I also compared the mRNA expression of three transgenic mouse models (DM2-KI, HSA-CTG and HSA-CCTG) with human DM patient muscle biopsy samples. My novel integrated comparative analysis strategy revealed widespread mRNA and miRNA misregulation in DM patients. RNA-seq analysis revealed no differential expression of DMPK, CNBP, MBNL1, MBNL2, MBNL3 and CUBP1 genes. I report massive misregulation of cytoskeletal signaling, insulin resistance and calcium signaling in both DM1 and DM2 patients. I identified unique negative enrichment of eukaryotic translation initiation factor 2 (EIF2) signaling, mitochondrial dysfunction, mammalian target of rapamycin (mTOR) signaling and regulation of eukaryotic translation initiation factor 4 (EIF4) in DM1 patients. Up regulation of actin cytoskeletal signaling mediated via RhoGTPases family proteins is a novel finding in DM2 patients and DM2-KI mouse model. I also report the novel activation of Nuclear factor kB (NF-kB), hypoxia-inducible factor-1 alpha (HIF1A), canonical beta catenin (CTNNB1) transcription factors in skeletal muscles of both DM1 and DM2 patients suggesting increased instance of both muscular atrophy as well as at the same time activation of post muscular atrophic remodeling and functional differentiation in DM patients. miRNA expression analysis identified a panel of uniquely expressed miRNAs that can serve as biomarkers for identification of muscular dystrophy and insulin resistance in DM patients. Moreover, the target prediction analysis identified crucial miRNA/mRNA interactions and outlined distinct targeting of genes regulating actin cytoskeletal signaling, calcium signaling, cardiac hypertrophy signaling and axonal guidance signaling. The massive adaptation of signaling pathways provides evidence of their significant impact in the DM disease pathogenesis. My findings showed that myotonic dystrophy is a complex disorder that has distinct mRNA, miRNA and protein expression pointing to the diagnostic and therapeutic potential of the expression profiling presented in this study.
Recommended Citation
Prasad, Nripesh, "Cellular processes regulating cytoskeletal signaling, insulin resistance and calcium signaling are commonly misregulated in Type 1 and Type 2 myotonic dystrophy patients" (2014). Dissertations. 36.
https://louis.uah.edu/uah-dissertations/36