• Heterogeneity and the genetics of bipolar disorder

      Faraone, Stephen V.; Tsuang, Ming T. (Wiley, 2003-10-30)
    • IDENTIFICATION OF p53-MEDIATED NEUROGENOMIC RESPONSES TO ETHANOL USING IN VIVO AND IN VITRO MODELS OF FETAL ALCOHOL SPECTRUM DISORDER

      Camargo, Maria (2016)
      Fetal Alcohol Spectrum Disorder (FASD) is a serious public health concern affecting 3.6% of the US population. One avenue to achieve a decrease in the prevalence of FASD is for scientific research to identify cellular mechanisms of action of imbibed alcohol and propose solutions to treat or prevent the damage done. Here we present our investigation into the molecular consequences of ethanol exposure in mouse brain cells and mouse neural stem cell cultures. Specifically, we tested the hypothesis that p53 mediates the neurogenomic response to ethanol exposure in brain cells in the somatosensory cortex, hippocampus and neural stem cells. p53 is a versatile transcription factor well known for inducing cell death in cancer cells. We identified the apoptosis pathway as being changed in a p53-related manner only in the CA1 subregion of the hippocampus, based on expression changes in Casp2, Cdk1, and Stat1. Overall, the regions interrogated revealed that p53’s cellular response is heterogeneous. In the somatosensory cortex and hippocampus a subset of gene expression changes occurred depending on both ethanol exposure and the presence of p53: Ephb1in layer 2/3; Ctgf in layer 5; Camk1 in layer 6; Cdk1, Casp2, Cdk1, and Stat1 in the CA1; and Camk1 in the DG. In regards to the specific mRNAs that changed, they differed in the brain regions and cell cultures, but we did observe that neuronal and developmental genes were the most significantly changed upon ethanol exposure. In addition, we also identified that the category of genes whose methylation pattern was changed after ethanol exposure are related to basic neuronal functions. Neural cells also appeared to be engaged in a challenging response to ethanol because DNA repair proteins Ercc1, Hus1, and Rad51 alter their DNA binding after ethanol exposure. In addition, we identified that p53 transcription factor changes its DNA binding in response to ethanol exposure. In conclusion, we identified that neural p53 signaling is measurably perturbed by ethanol exposure.
    • Identification of TIMP2 as the first secretory co-chaperone of eHSP90

      Dimitra Bourboulia; Baker-Williams, Alexander J. (2021)
      Heat Shock Protein- 90 (HSP90) is an essential molecular chaperone. HSP90 relies on its intrinsic ATPase activity as well as interactions with co-chaperone proteins to chaperone its clients. HSP90 is also an extracellular protein, performing both a signaling and chaperoning role. Extracellular client, matrix metalloproteinase-2 (MMP2) relies on HSP90 for its stability. MMP2 mediates extracellular matrix remodeling through its gelatinolytic activity. MMP2 activity is also tightly regulated by its endogenous inhibitor, the Tissue Inhibitor of Metalloproteinase-2 (TIMP2). At present how HSP90 performs its chaperoning role in the extracellular matrix is uncertain. In this thesis, I describe that TIMP2 acts as the first bona fide extracellular co-chaperone of eHSP90, and show that TIMP2 is a stress inducible protein. I describe how TIMP2 directly interacts with HSP90, and how TIMP2 decelerates the HSP90 ATPase cycle. TIMP2 also sensitizes HSP90 to both ATP and N-terminal pharmaceuticals. Overall, TIMP2 acts as both a scaffold and a disruptor of the client/chaperone relationship between MMP2 and HSP90, performing both a HSP90 co-chaperone and MMP2 inhibitor role, non-mutually exclusively. The activatory co-chaperone AHA1 competes with TIMP2 for HSP90 binding. TIMP2 and AHA1 are able to form two independent ternary complexes with MMP2 and HSP90; as a result, the TIMP2 complex is MMP2 proteolytically inactive and the AHA1, active. This competition is further described in vivo where it can be inhibited by both _AHA1 antibodies and TIMP2 AHA1 antibodies and TIMP2 exogenous protein treatments, whilst induced following AHA1 protein and _AHA1 antibodies and TIMP2 TIMP2 antibody treatments. Finally, the role of phos-Y-TIMP2 was examined in relation to its interaction with HSP90. To address this, a novel methodology to purify hTIMP2 from E.Coli without previously necessary refolding strategies in a scale-able manner suitable for therapeutic TIMP2 treatments, was developed. Wild type recombinant human TIMP2 and phospho-mutants Y90E, Y90F, and TE (Y62E, Y90E, Y165E) were purified, were inhibitory towards MMP2, and modulated TIMP2 interaction with HSP90. Taken together, I demonstrate how extracellular HSP90 is regulated by co-chaperones to facilitate the chaperoning of pro-invasive client, MMP2. It further shows ways in which we can manipulate this system to promote an inactive MMP2 protease, a key strategy in cancer therapeutics.
    • Impact of Psychometrically Defined Deficits of Executive Functioning in Adults With Attention Deficit Hyperactivity Disorder

      Biederman, Joseph; Petty, Carter; Fried, Ronna; Fontanella, Jessie; Doyle, Alysa E.; Seidman, Larry J.; Faraone, Stephen V. (American Psychiatric Association Publishing, 2006-10)
      Objective: The association between deficits in executive functioning and functional outcomes was examined among adults with attention deficit hyperactivity disorder (ADHD). Method: Subjects were adults who did (N=213) and did not (N=145) meet DSMIV criteria for ADHD. The authors defined having deficits in executive functioning as having at least two measures of executive functioning with scores 1.5 standard deviations below those of matched comparison subjects. Results: Significantly more adults with ADHD had deficits of executive functioning than comparison subjects. Deficits of executive functioning were associated with lower academic achievement, irrespective of ADHD status. Subjects with ADHD with deficits of executive functioning had a significantly lower socioeconomic status and a significant functional morbidity beyond the diagnosis of ADHD alone. Conclusions: Psychometrically defined deficits of executive functioning may help identify a subgroup of adults with ADHD at high risk for occupational and academic underachievement. More efforts are needed to identify cost-effective approaches to screen individuals with ADHD for deficits of executive functioning.
    • Impact of Tic Disorders on ADHD Outcome Across the Life Cycle: Findings From a Large Group of Adults With and Without ADHD

      Spencer, Thomas J.; Biederman, Joseph; Faraone, Stephen V.; Mick, Eric; Coffey, Barbara; Geller, Daniel; Kagan, Jake; Bearman, Sarah Kate; Wilens, Timothy (American Psychiatric Association Publishing, 2001-04)
      Objective: The impact of tic disorders on the outcome of attention deficit hyperactivity disorder (ADHD) remains a subject of high scientific and clinical interest. To evaluate the impact of comorbid ADHD and tic disorders from a lifespan perspective, the authors systematically examined data from adults with and without ADHD. Method: They comprehensively evaluated 312 consecutively referred adults with ADHD and 252 comparison subjects without ADHD. Tic disorders were characterized along with a wide range of neuropsychiatric correlates, including other comorbid disorders as well as indexes of function in the domains of school, cognition, and interpersonal functioning. Results: A significantly greater proportion of adults with ADHD (12%) than those without ADHD (4%) had tic disorders. Tic disorders followed a mostly remitting course and had little impact on functional capacities. In addition, tic disorders were not associated with stimulant use. Conclusions: These findings in adults with ADHD confirm and extend previous findings in young subjects with ADHD, documenting that although individuals with ADHD are at greater risk for tic disorders, the presence of tic disorders has a limited impact on ADHD outcome.
    • Influence of Gender on Attention Deficit Hyperactivity Disorder in Children Referred to a Psychiatric Clinic

      Biederman, Joseph; Mick, Eric; Faraone, Stephen V.; Braaten, Ellen; Doyle, Alysa; Spencer, Thomas; Wilens, Timothy E.; Frazier, Elizabeth; Johnson, Mary Ann (American Psychiatric Association Publishing, 2002-01)
      Objective: The substantial discrepancy in the male-to-female ratio between clinic-referred (10 to 1) and community (3 to 1) samples of children with attention deficit hyperactivity disorder (ADHD) suggests that gender differences may be operant in the phenotypic expression of ADHD. In this study the authors systematically examined the impact of gender on the clinical features of ADHD in a group of children referred to a clinic. Method: The study included 140 boys and 140 girls with ADHD and 120 boys and 122 girls without ADHD as comparison subjects. All subjects were systematically assessed with structured diagnostic interviews and neuropsychological batteries for subtypes of ADHD as well as emotional, school, intellectual, interpersonal, and family functioning. Results: Girls with ADHD were more likely than boys to have the predominantly inattentive type of ADHD, less likely to have a learning disability, and less likely to manifest problems in school or in their spare time. In addition, girls with ADHD were at less risk for comorbid major depression, conduct disorder, and oppositional defiant disorder than boys with ADHD. A statistically significant gender-by-ADHD interaction was identified for comorbid substance use disorders as well. Conclusions: The lower likelihood for girls to manifest psychiatric, cognitive, and functional impairment than boys could result in gender-based referral bias unfavorable to girls with ADHD
    • The influence of genes on “positive valence systems” constructs: A systematic review

      Hess, Jonathan L.; Kawaguchi, Daniel M.; Wagner, Kayla E.; Faraone, Stephen V.; Glatt, Stephen J. (Wiley, 2015-09-14)
      The Research Domain Criteria (RDoC) address three types of aggression: frustrative non-reward, defensive aggression and offensive/proactive aggression. This review sought to present the evidence for genetic underpinnings of aggression and to determine to what degree prior studies have examined phenotypes that fit into the RDoC framework. Although the constructs of defensive and offensive aggression have been widely used in the animal genetics literature, the human literature is mostly agnostic with regard to all the RDoC constructs. We know from twin studies that about half the variance in behavior may be explained by genetic risk factors. This is true for both dimensional, trait-like, measures of aggression and categorical definitions of psychopathology. The non-shared environment seems to have a moderate influence with the effects of shared environment being unclear. Human molecular genetic studies of aggression are in an early stage. The most promising candidates are in the dopaminergic and serotonergic systems along with hormonal regulators. Genome-wide association studies have not yet achieved genome-wide significance, but current samples are too small to detect variants having the small effects one would expect for a complex disorder. The strongest molecular evidence for a genetic basis for aggression comes from animal models comparing aggressive and non-aggressive strains or documenting the effects of gene knockouts. Although we have learned much from these prior studies, future studies should improve the measurement of aggression by using a systematic method of measurement such as that proposed by the RDoC initiative. © 2015 Wiley Periodicals, Inc.
    • Influence of Parental SUD and ADHD on ADHD in their Offspring: Preliminary Results from a Pilot-controlled Family Study

      Wilens, Timothy E.; Hahesy, Amy L.; Biederman, Joseph; Bredin, Elizabeth; Tanguay, Sarah; Kwon, Anne; Faraone, Stephen V. (Wiley, 2005-03)
      As part of a pilot-controlled family-based study of the children of parents with and without substance use disorders (SUD), the influence of parental SUD and ADHD on the risk for ADHD in offspring was evaluated. Using structured psychiatric interviews, 96 families (183 youth; mean age 11.6 years) were assessed. To evaluate the effect of parental ADHD and SUD, the offspring were stratified into four groups based on parental status: children of parents with neither ADHD nor SUD, children of parents with SUD only, children of parents with ADHD only, and children of parents with both ADHD and SUD. Using generalized estimating equation models, parental SUD and ADHD were used to predict ADHD in the offspring. The rate of children with ADHD increased among children of parents with neither disorder (3%), children of parents with SUD (13%), children of parents with ADHD (25%), and children of parents with both ADHD and SUD (50%) (p ¼ :001). Children of parents with ADHD or ADHD plus SUD were more likely to have ADHD in comparison to children of parents with neither diagnosis (p < 0:05). Children of parents with ADHD plus SUD were at greater risk of ADHD in comparison to children of parents with SUD only (p ¼ 0:01). Despite the small sample size, the results of this study seem to suggest that the offspring of SUD or ADHD parents are at elevated risk for ADHD compared to controls. The offspring of parents with both ADHD and SUD appear to be at the highest risk for ADHD, highlighting the need for careful screening of this group of youth for ADHD. Replication studies clarifying the nature and strength of the association are necessary.
    • Informativeness of Self-Reports of ADHD Symptoms in Monitoring Response to Stimulant Treatment in Clinically Referred Adults With ADHD

      Biederman, Joseph; Fitzgerald, Maura; Spencer, Thomas J.; Adler, Lenard A.; Abrams, Jessica; Biederman, Itai; Faraone, Stephen V. (SAGE Publications, 2018-05-26)
      To investigate the informativeness of self-reports of ADHD symptoms in adults with ADHD in the clinical setting. Method: Subjects were clinically referred adults aged 19 years to 67 years of age of both sexes (N = 54). All subjects were on stable doses of stimulant and were considered responders to treatment. ADHD symptoms were assessed using the ADHD Investigator Symptom Rating Scale (AISRS) and the ADHD Self-Report Scale (ASRS). Spearman’s rank correlations were used to assess the correlations between clinician-assessed ADHD and patients’ self-reports. Results: Spearman’s rank correlation analysis found evidence of a strong, positive association between total scores on the AISRS and the ASRS (rs = .65, df = 52, p < .001). Conclusion: Results have important implications for the management and monitoring of treatment response in the clinical setting through patients’ self-report.(J. of Att. Dis. 2020; 24(3) 420-424)
    • Investigating the Role of Paxillin in Mammary Gland Morphogenesis and Breast Cancer Progression

      Turner, Christopher; Xu, Weiyi (2020)
      Breast cancer is one of the most invasive cancers among women. Understanding the mechanisms contributing to breast cancer progression may identify potential ways to prevent and cure the disease. Meanwhile, mammary gland morphogenesis shares similar mechanisms to allow the ducts to invade and occupy the fat pad. Thus, it is equally important to investigate the normal mammary gland development as breast tumor progression. Paxillin, as a focal adhesion scaffold protein, has previously been implicated in multiple types of cancer cell migration and invasion through its role in cell- ECM signaling. Herein, I utilized a novel paxillin conditional knockout mouse model and paxillin knockout mouse crossed with PyMT breast tumor mouse model to show that paxillin is critical for both mammary gland morphogenesis and breast tumor progression. In Chapter 2, by evaluating the developing mammary gland morphology with immunohistochemistry and the three-dimensional cultured mammary organoids and acini, a critical role of paxillin was shown in facilitating apical-basal polarity formation in the luminal epithelial cells in part, through its control of HDAC6 activity and associated microtubule acetylation. Correct polarization and columnar shape of the epithelial cells potentially contributes to lumen formation and branching of the ducts. Investigation in Chapter 3 highlights a crucial role of paxillin in breast cancer invasion and distant organ metastasis, but did not affect the primary tumor growth rate. Further analysis revealed that paxillin is required for the endocytosis and recycling of E- cadherin, which is important for the maintenance of Adherens junction equilibrium during cancer cell collective migration. This thesis characterizes the roles for paxillin in mammary gland morphogenesis and breast cancer progression and reveals the importance of paxillin-dependent apical trafficking in normal epithelial cells, and E-cadherin trafficking in collective migrating tumor cells. Together, this work highlights a trafficking-dependent mechanism for paxillin during both physiologic and pathologic processes in the mammary gland.
    • Investigation of parent-of-origin effects in ADHD candidate genes

      Kim, Jang Woo; Waldman, Irwin D.; Faraone, Stephen V.; Biederman, Joseph; Doyle, Alysa E.; Purcell, Shaun; Arbeitman, Lori; Fagerness, Jesen; Sklar, Pamela; Smoller, Jordan W. (Wiley, 2007)
    • JUNCTIONAL ARMADILLO (β-CATENIN) MAINTAINS PROPER TISSUE ARCHITECTURE DURINGDROSOPHILAEYE DEVELOPMENT

      Pignoni, Francesca; DeSantis, Dana F (2020)
      Formation of thecompoundeye of Drosophilarequires carefully orchestrated developmental events that occur in its progenitor epithelium, the eye imaginal disc.This tissue is composed of two continuous, apposed epithelia: the disc proper epithelium (DpE), which forms the retina, and the peripodial epithelium (PE), which ultimately forms head cuticle. In this work, I describe an armadillo (b-catenin)loss-of-function condition in which the developing DpEis disrupted and displays a phenotype that I call“retinalshift”. This developmental phenotype ultimately results in abnormal fly eye morphology that is incompatible with compound eye vision.I uncover a role for the PE in maintaining proper retinal epithelium morphology during eye formation and trace the molecular mechanism to the regulation of Hippo-Yki pathway in PE cells by the function of Armadillo at the adherens junctions.
    • Laboratory-Observed Behavioral Disinhibition in the Young Offspring of Parents With Bipolar Disorder: A High-Risk Pilot Study

      Hirshfeld-Becker, Dina R.; Biederman, Joseph; Henin, Aude; Faraone, Stephen V.; Cayton, Gabrielle A.; Rosenbaum, Jerrold F. (American Psychiatric Association Publishing, 2006-02)
      Objective: This study tested whether behavioral disinhibition is more prevalent among offspring of parents with bipolar disorder than among offspring of parents without bipolar disorder. Method: The authors conducted a secondary analysis of data from a preexisting high-risk study of offspring at risk for panic disorder and depression (N=278) that had included some children with parents who had bipolar disorder (N=34). Children (ages 2–6) had been classified as behaviorally inhibited, disinhibited, or neither in laboratory assessments. Results: Offspring of bipolar parents had significantly higher rates of behavioral disinhibition than offspring of parents without bipolar disorder. Behavioral inhibition did not differ between groups. Differences were not accounted for by parental panic disorder or major depression or by parental history of attention deficit hyperactivity disorder, conduct disorder, antisocial personality, or substance use disorders. Conclusions: Results suggest a familial link between bipolar disorder in parents and behavioral disinhibition in their offspring. Behavioral disinhibition may be a familially transmitted predisposing factor for dysregulatory distress later in life.
    • Lack of Association Between Behavioral Inhibition and Psychosocial Adversity Factors in Children at Risk for Anxiety Disorders

      Hirshfeld-Becker, Dina R.; Biederman, Joseph; Faraone, Stephen V.; Segool, Natasha; Buchwald, Jennifer; Rosenbaum, Jerrold F. (American Psychiatric Association Publishing, 2004-03)
      Objective: In a previous controlled study of offspring at risk for anxiety disorders, the authors found that parental panic disorder with comorbid major depression was associated with child behavioral inhibition, the temperamental tendency to be quiet and restrained in unfamiliar situations. To explore whether this association was mediated by environmental factors, the authors examined associations between psychosocial adversity variables and behavioral inhibition in this group of children. Method: Subjects included 200 offspring of parents with panic disorder and/or major depression and 84 comparison children of parents without mood or anxiety disorders. Behavioral inhibition was assessed through laboratory observations. The associations between behavioral inhibition and the following psychosocial factors were examined: socioeconomic status; an index of adversity factors found in previous studies to be additively associated with child psychopathology; family intactness, conflict, expressiveness, and cohesiveness; exposure to parental psychopathology; sibship size; birth order; and gender. Results: The results showed no associations between behavioral inhibition and any of the psychosocial factors in the study group as a whole, despite adequate power to detect medium effect sizes. Among low-risk comparison children only, some definitions of behavioral inhibition were associated with low socioeconomic status, low family cohesion, and female gender. Conclusions: The results suggest that the psychosocial adversity factors examined in this study do not explain the previous finding that offspring of parents with panic disorder are at high risk for behavioral inhibition.
    • Lack of Association Between Parental Alcohol or Drug Addiction and Behavioral Inhibition in Children

      Biederman, Joseph; Hirshfeld-Becker, Dina R.; Rosenbaum, Jerrold F.; Perenick, Sarah G.; Wood, Julia; Faraone, Stephen V. (American Psychiatric Association Publishing, 2001-10)
      Objective: “Behavioral inhibition to the unfamiliar” has been proposed as a precursor to anxiety. A recent study proposed that it may also be a precursor to alcoholism. The authors sought to replicate the latter finding through a secondary analysis of data from a large study of young children (age 2–6 years)—offspring of parents with panic and depressive disorders—who had been assessed for behavioral inhibition through laboratory-based observations. Method: The offspring were stratified on the basis of presence or absence of parental lifetime history of DSM-III-R alcohol dependence (N=115 versus N=166, respectively) or drug dependence (N=78 versus N=203). The rates of behavioral inhibition were then compared between groups. Results: Despite adequate power to detect associations, neither parental alcohol dependence nor drug dependence was associated with a higher risk for behavioral inhibition in the offspring. Conclusions: These results are not consistent with the hypothesis linking behavioral inhibition to addictions