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Coming dissertations at MedFak

  • Investigating histidine-rich glycoprotein and T cell-specific adaptor as potential biomarkers and therapeutic targets Author: Tor Persson Skare Link: Publication date: 2021-11-01 13:15

    The endothelial cell (EC), the most important cell type in blood vessels, lines the vessel wall and provides vessel integrity. EC function is tightly regulated, and its dysregulation is a key element in many diseases including cardiovascular disease, cancer and several diseases of the eye. 

    This thesis investigates the prognostic and therapeutic potential of two proteins: histidine-rich glycoprotein (HRG) and T cell-specific adaptor protein (TSAd). HRG is an abundant hepatocyte-derived protein, involved in many biological processes including hemostasis and fibrinolysis, inflammation, and angiogenesis. TSAd is an adapter protein downstream of vascular endothelial growth factor (VEGF) receptor 2, required for VEGF-A induced vascular permeability. 

    In Paper I HRG-based therapy is tested in glioma using an HRG-encoding non-replicating adenovirus vector delivered orthotopically in the GL261 mouse glioma model. HRG treatment results in reduced tumor growth and increased vessel perfusion. Further mechanistic analysis reveals that stanniocalcin 2 (STC2) is a binding partner of HRG on the surface of inflammatory cells. 

    Paper II investigates the potential of HRG as a prognostic biomarker in mature B cell lymphomas using tissue microarrays of human lymphoma samples. RNAscope is employed to identify tumor cell expression of HRG, and complementing immunostainings reveal that high HRG expression is a marker of improved overall survival for patients with marginal zone lymphoma, independent of age, stage and sex. 

    In Paper III the interaction of HRG and STC2 is characterized further using the human histiocytic lymphoma cell line U937 that can differentiate towards a macrophage-like cell type after stimulation with vitamin D3. The bioactivity of recombinant HRG and STC2 is ensured by testing their effects on phagocytosis in U937 cells.  Quartz crystal microbalance analysis reveals that HRG binds STC2 with high affinity in a conformation dependent manner. 

    Paper IV describes a high throughput screen for a small chemical compound capable of blocking VEGF-induced vascular permeability by binding TSAd. Screening of approximately 22000 compounds results in the discovery of a lead compound that binds TSAd and blocks VEGF-induced permeability in an ex-vivo assay.

    In summary, the papers presented in this thesis describe different strategies to investigate the role of HRG and TSAd on ECs and how this information can be applied therapeutically. The results confirm the importance of EC biology in disease, and the clinical potential HRG and TSAd as therapeutics or as biomarkers.

  • The relationship between overweight and depression in view of genes, environment and their joint influence Author: Sofia H. Kanders Link: Publication date: 2021-10-29 09:24

    Obesity and depression are known to often go hand in hand, but is this due to our genetic heritage, environmental factors or a combination thereof? With a neuroscientific approach, I have investigated the relationship between obesity and depression with the aim of bridging the different levels of research available in order to better understand this complex topic. 

    Using data from a longitudinal cohort with adults, we analysed the genetic contribution to antidepressant response in Study I. The association between antidepressant treatment and changes in body mass index, waist circumference and fat mass was assessed in Study II. In Study III, the importance of bullying victimization for the relationship between obesity and depression was analysed using a longitudinal cohort with adolescents. Lastly, the moderating effect from breastfeeding duration on the relation between a known obesity associated gene and body mass index among adolescents and young adults was examined in Study IV.

    The bidirectional relationship between obesity and depression is derived from several joint processes and mechanisms such as the stress system and symptomatology overlap with strong environmental influences affecting both disorders, plausibly through epigenetic processes. Even though overweight and obesity were associated with depressive symptoms, one even more important environmental factor for the development of symptoms was bullying victimization – a risk factor that persisted after six years of follow-up. The genetic contribution to these complex disorders from individual variations is small in most cases, but with a credible additive effect and with environmental factors as important moderators of these relationships. One such moderator is breastfeeding duration, which was found to contribute to the relationship between FTO and future BMI with different patterns for the individual variants, which supports the differential susceptibility hypothesis. Finally, when AD treatment is used, the patient should be monitored regularly, both regarding depressive symptoms as well as obesity-related measurements.

    Overall, it is of high importance to focus on prevention because the frequently chronic course of obesity, as well as depression, has a high burden on individuals, as well as on society.

  • Depressive Symptoms Among Adolescents and Young Adults : Psychometrics and the Influence of Family Environment, and Candidate Gene–environment Interactions Author: Rebecka Keijser Link: Publication date: 2021-10-27 10:59

    The overall aims of this thesis were to evaluate the psychometric properties of a questionnaire designed to evaluate parenting styles, and to study how depressive symptoms among adolescents and young adults may vary depending on the family environment and candidate gene–environment interaction (cG×E).

    The study sample consisted of participants (born during 1997 or 1999), and their caregivers from the Survey of Adolescent Life in Västmanland Cohort Study. This thesis included data from 2012 when the participants were 13 and 15 years old (Wave I: DNA collection), 2015 at ages 16 and 18 years (Wave II: Parenting styles, parental depression, depressive symptoms, early life stress i.e., ELS) and 2018 at ages 19 and 21 years (Wave III: Depressive symptoms).

    Paper I: A good model fit was obtained for the Parent as Social Context Questionnaire (PASCQ) parent and adolescent versions through psychometric evaluations. Paper II: Positive and negative parenting styles were associated with fewer or more depressive symptoms among adolescents and young adults, respectively. Parental depression×sex was associated with more depressive symptoms, preponderant among female adolescents. The findings were not significant among young adults. Paper III: A significant cG×E effect between oxytocin receptor single-nucleotide polymorphism (SNP) rs6770632 and negative parenting style on depressive symptoms among young adults was found. Paper IV: Significant cG×E effects were found for the FKBP5 SNPs rs1360780, rs4713916, rs7748266 and rs9394309 moderated by ELS and positive parenting style on depressive symptoms among young adults.

    These findings suggest that parenting styles may be measured with the PASCQ and that depressive symptoms among adolescents and young adults seem to vary dependent on the family environment and cG×E effects. However, the cG×E effects may be more central for some individuals depending on differences in diathesis- or sensitivity towards the family environment. The variance in depressive symptoms may therefore contain diathesis stress and differential susceptibility effects regarding the cG×E interaction. The insight gained from this thesis provides a foundation for future research and contributes to research areas such as parenting research and the understanding of biological factors behind depressive symptomology among adolescents and young adults.