Browsing by Subject "Pathways"

Now showing 1 - 6 of 6
  • Thumbnail Image
    Item
    Alternative Assembly Pathways of the 20S Proteasome and Non-canonical Complexes
    (2018-12) Panfair, Dilrajkaur; Balakrishnan, Lata; Kusmierczyk, Andrew; Randall, Stephen; Rubenstein, Eric; Anderson, Gregory
    The 20S proteasome, a multi-subunit protease complex, present in all domains of life and some orders of bacteria, is involved in degradation of the majority of cellular proteins. Structurally, it is made of α and β subunits arranged in four heptameric rings, with inner two β-rings sandwiched between outer two α-rings. The 20S proteasome in prokaryotes usually has one type of α and one type of β subunits, whereas eukaryotes have seven distinct types of α and seven distinct types of β subunits. Unlike the highly conserved structure of proteasome, its assembly pathway is different across the domains. In archaea and eukaryotes, proteasome assembly begins with α subunit interactions leading to the α-ring formation. By contrast, bacterial proteasome assembly pathway bypasses the α-ring formation step by initiating assembly through an α and β subunit interaction first. These early interactions are not well understood due to their highly rapid and dynamic nature. This dissertation focused on understanding the early events in proteasome assembly and contributed three significant findings. First, the archaeal proteasome assembly can also begin without formation of α-rings, demonstrating the coexistence of a bacterial-like assembly pathway. Second, a novel assembly intermediate was identified in yeast, and its composition argues for the presence of a similar α-ring independent assembly pathway. Third, the assembly chaperone Pba3-Pba4 prevents the formation of high molecular weight complexes arising from spontaneous and non-productive interactions among the α subunits. These findings provide a broader understanding of proteasome biogenesis and suggest considering proteasome assembly event as a network of interactions rather than a linear pathway. The results also shed light on assembly chaperone’s contribution in increasing the efficiency of proteasome assembly by streamlining the productive interactions.
  • Thumbnail Image
    Item
    Chronic alcohol exposure alters gene expression in HepG2 cells
    (Wiley, 2012) Pochareddy, Sirisha; Edenberg, Howard J.; Biochemistry and Molecular Biology, School of Medicine
    Background: The liver is the primary site of alcohol metabolism and is highly vulnerable to injuries due to chronic alcohol abuse. Several molecular mechanisms, including oxidative stress and altered cellular metabolism, have been implicated in the development and progression of alcoholic liver disease. We sought to gain further insight into the molecular pathogenesis by studying the effects of ethanol exposure on the global gene expression in HepG2 cells. Methods: HepG2 cells were cultured in the presence or absence of 75 mM ethanol for 9 days, with fresh media daily. Global gene expression changes were studied using Affymetrix GeneChip(®) Human Exon 1.0 ST Arrays. Gene expression differences were validated for 13 genes by quantitative real-time RT-PCR. To identify biological pathways affected by ethanol treatment, differentially expressed genes were analyzed by Ingenuity Pathway Analysis software. Results: Long-term ethanol exposure altered the expression of 1,093 genes (false discovery rate ≤ 3%); many of these changes were modest. Long-term ethanol exposure affected several pathways, including acute phase response, amino acid metabolism, carbohydrate metabolism, and lipid metabolism. Conclusions: Global measurements of gene expression show that a large number of genes are affected by chronic ethanol, although most show modest effect. These data provide insight into the molecular pathology resulting from extended alcohol exposure.
  • Thumbnail Image
    Item
    Convergent functional genomics of schizophrenia: from comprehensive understanding to genetic risk prediction
    (Springer Nature, 2012) Ayalew, M.; Le-Niculescu, H.; Levey, D. F.; Jain, N.; Changala, B.; Patel, S. D.; Winiger, E.; Breier, A.; Shekhar, A.; Amdur, R.; Koller, D.; Nurnberger, J. I.; Corvin, A.; Geyer, M.; Tsuang, M. T.; Salomon, D.; Schork, N. J.; Fanous, A. H.; O’Donovan, M. C.; Niculescu, A. B.; Psychiatry, School of Medicine
    We have used a translational convergent functional genomics (CFG) approach to identify and prioritize genes involved in schizophrenia, by gene-level integration of genome-wide association study data with other genetic and gene expression studies in humans and animal models. Using this polyevidence scoring and pathway analyses, we identify top genes (DISC1, TCF4, MBP, MOBP, NCAM1, NRCAM, NDUFV2, RAB18, as well as ADCYAP1, BDNF, CNR1, COMT, DRD2, DTNBP1, GAD1, GRIA1, GRIN2B, HTR2A, NRG1, RELN, SNAP-25, TNIK), brain development, myelination, cell adhesion, glutamate receptor signaling, G-protein-coupled receptor signaling and cAMP-mediated signaling as key to pathophysiology and as targets for therapeutic intervention. Overall, the data are consistent with a model of disrupted connectivity in schizophrenia, resulting from the effects of neurodevelopmental environmental stress on a background of genetic vulnerability. In addition, we show how the top candidate genes identified by CFG can be used to generate a genetic risk prediction score (GRPS) to aid schizophrenia diagnostics, with predictive ability in independent cohorts. The GRPS also differentiates classic age of onset schizophrenia from early onset and late-onset disease. We also show, in three independent cohorts, two European American and one African American, increasing overlap, reproducibility and consistency of findings from single-nucleotide polymorphisms to genes, then genes prioritized by CFG, and ultimately at the level of biological pathways and mechanisms. Finally, we compared our top candidate genes for schizophrenia from this analysis with top candidate genes for bipolar disorder and anxiety disorders from previous CFG analyses conducted by us, as well as findings from the fields of autism and Alzheimer. Overall, our work maps the genomic and biological landscape for schizophrenia, providing leads towards a better understanding of illness, diagnostics and therapeutics. It also reveals the significant genetic overlap with other major psychiatric disorder domains, suggesting the need for improved nosology.
  • Thumbnail Image
    Item
    Functional microRNAs in Alzheimer’s disease and cancer: differential regulation of common mechanisms and pathways
    (Frontiers Media, 2013-01-17) Holohan, Kelly N.; Lahiri, Debomoy K.; Schneider, Bryan P.; Foroud, Tatiana; Saykin, Andrew J.; Medical and Molecular Genetics, School of Medicine
    Two of the main research priorities in the United States are cancer and neurodegenerative diseases, which are attributed to abnormal patterns of cellular behavior. MicroRNAs (miRNA) have been implicated as regulators of cellular metabolism, and thus are an active topic of investigation in both disease areas. There is presently a more extensive body of work on the role of miRNAs in cancer compared to neurodegenerative diseases, and therefore it may be useful to examine whether there is any concordance between the functional roles of miRNAs in these diseases. As a case study, the roles of miRNAs in Alzheimer's disease (AD) and their functions in various cancers will be compared. A number of miRNA expression patterns are altered in individuals with AD compared with healthy older adults. Among these, some have also been shown to correlate with neuropathological changes including plaque and tangle accumulation, as well as expression levels of other molecules known to be involved in disease pathology. Importantly, these miRNAs have also been shown to have differential expression and or functional roles in various types of cancer. To examine possible intersections between miRNA functions in cancer and AD, we review the current literature on these miRNAs in cancer and AD, focusing on their roles in known biological pathways. We propose a pathway-driven model in which some molecular processes show an inverse relationship between cancer and neurodegenerative disease (e.g., proliferation and apoptosis) whereas others are more parallel in their activity (e.g., immune activation and inflammation). A critical review of these and other molecular mechanisms in cancer may shed light on the pathophysiology of AD, and highlight key areas for future research. Conclusions from this work may be extended to other neurodegenerative diseases for which some molecular pathways have been identified but which have not yet been extensively researched for miRNA involvement.
  • Thumbnail Image
    Item
    Hope as a predictor of physical activity behavior in middle-aged and older adults with musculoskeletal pain
    (Frontiers Media, 2025-04-29) Kessler, Renee; Teegardin, Monica M.; Kaleth, Anthony S.; Naugle, Kelly M.; Psychology, School of Science
    Background: Musculoskeletal pain is a barrier to physical activity, enhancing functional decline in older adults. Thus, identifying psychological factors that promote physical activity in older adults with musculoskeletal pain is warranted. Prior research shows that the psychological construct of hope predicts the frequency of exercise in healthy younger adults. However, the impact of hope on physical activity behavior in an older population with clinical pain is unknown. This observational study was designed to determine whether hope predicted self-reported and objective physical activity levels in older adults with musculoskeletal pain. Methods: Fifty-two middle-aged to older adults (age range 55-85 years; 67% female) completed all assessments. Participants completed questionnaires to assess hope (Adult Hope Scale), self-reported physical activity (Physical Activity Scale for the Elderly), bodily pain (SF-36), kinesiophobia (Tampa Scale of Kinesiophobia), and pain catastrophizing (Pain Catastrophizing Scale). Participants also wore accelerometers on the hip for one week to objectively measure physical activity levels. Correlations were conducted to determine relationships between variables. Hierarchical regressions were conducted to determine whether hope predicted self-reported and objective physical activity levels after controlling for relevant demographics, pain, and other psychological variables. Results: After controlling for bodily pain, hope significantly predicted self-reported physical activity and was associated with greater physical activity levels. Bodily pain, but not hope, significantly predicted average daily steps derived from the accelerometer. Decreased bodily pain was associated with more daily steps. Conclusion: These findings suggest that trait hope could be a key psychological predictor of self-reported physical activity in older adults with musculoskeletal pain. Clarifying the role of hope in the physical activity behavior of older adults could present a novel target for intervention.
  • Thumbnail Image
    Item
    Targeting SHP2 phosphatase in hematological malignancies
    (Taylor & Francis, 2022) Kanumuri, Rahul; Pasupuleti, Santhosh Kumar; Burns, Sarah S.; Ramdas, Baskar; Kapur, Reuben; Pediatrics, School of Medicine
    Introduction: Src homology-2-containing protein tyrosine phosphatase 2 (SHP2) is a ubiquitously expressed, non-receptor protein tyrosine phosphatase encoded by the PTPN11 gene. Gain-of-function (GOF) mutations in PTPN11 are associated with the development of various hematological malignancies and Noonan syndrome with multiple lentigines (NS-ML). Preclinical studies performed with allosteric SHP2 inhibitors and combination treatments of SHP2 inhibitors with inhibitors of downstream regulators (such as MEK, ERK, and PD-1/PD-L1) demonstrate improved antitumor benefits. However, the development of novel SHP2 inhibitors is necessary to improve the therapeutic strategies for hematological malignancies and tackle drug resistance and disease relapse. Areas covered: This review examines the structure of SHP2, its function in various signaling cascades, the consequences of constitutive activation of SHP2 and potential therapeutic strategies to treat SHP2-driven hematological malignancies. Expert opinion: While SHP2 inhibitors have exhibited promise in preclinical trials, numerous challenges remain in translation to the clinic, including drug resistance. Although PROTAC-based SHP2 degraders show better efficacy than SHP2 inhibitors, novel strategies need to be designed to improve SHP2-specific therapies in hematologic malignancies. Genome-wide CRISPR screening should also be used to identify molecules that confer resistance to SHP2 inhibitors. Targeting these molecules together with SHP2 can increase the target specificity and reduce drug resistance.