Alumni IZKF-Advanced Medical Scientists
Dr. Olivia Engmann
Advanced Medical Scientist-Programm 2019
Thema: "A novel pathway links caffeine effects with the circadian CLOCK system and mediates antidepressant action"
Zusammenfassung:
Circadian rhythm changes, reduced wakefulness and feelings of helplessness are symptoms of depression, the most common mental illness worldwide. Caffeine alters wakefulness and depressionsymptoms, but the underlying mechanisms are poorly understood. We are presenting a novel pathway, which links caffeine with the circadian CLOCK pathway via the dopaminergic phosphoprotein DARPP-32 in the mouse striatum. Phospho-T75-DARPP-32 disrupts binding of the circadian regulators CLOCK and BMAL 1 to chromatin and thereby regulates gene expression. T75A-DARPP-32 mutant mice show diminished caffeine-induced antidepressant effects in the awake phase. Furthermore, T75A-mutants are more light-dependent in their activity. We propose to study gene expression changes, which underlie altered depression-like behaviors in T75A-DARPP-32 mutants: 1. Through RNA-sequencing we will determine global gene expression changes induced by the DARPP-32:CLOCK pathway. 2. Using virus-mediated gene transfer, we will establish causality between gene products and their antidepressant effects. 3. We will characterize molecular and behavioral consequences of changed light cycles on the T75-DARPP-32 pathway. 4. Viral constructs will be used to improve light-cycle adaptations in vivo. This study may identify novel antidepressant targets and help to understand how circadian and depression-like behaviors are connected.
Dr. Holger Haselmann
Advanced Medeical Scientist-Programm 2019
Thema: "Epileptic seizures and synaptic network dysfunctions in autoimmune encephalitis"
Zusammenfassung:
Autoimmune encephalitis (AE) is a new group of neurological disorders with autoantibodies (aAB) against distinct neuronal surface antigens, including ionotropic and metabotropic receptors and synaptic clustering proteins. AE is characterized by rapidly progressive encephalitis or a chronic encephalopathy leading to cognitive dysfunction, confusion, psychotic symptoms and frequent seizures. Here, we aim to investigate the effect of aABs on the neuronal network and the balance of excitation and inhibition as a prerequisite for increased susceptibility to seizures. In a proof-ofconcept study we will first evaluate patient GluA2 AMPA receptor autoantibodies as epilepsy is a characteristic feature of this subtype of AE. Therefore, high resolution imaging and neurophysiological methods will be applied to investigate the effect of aABs on neuronal network function in-vitro in primary neurons and ex-vivo in an established mause model of AE. Dysbalance of the excitatory to inhibitory ratio will be determined on the single cell level and by recordings of the synaptic network aiming to explain the underlying pathophysiology of seizures in this subtype of AE. These experimental strategies will then be applied also to further subtypes of AE, e.g. with aABs to LGl1 and GABA receptors. The studies might contribute to development of optimized treatment strategies in controlling epilepsy in these disorders.
Dr. Andrea Kliewer
Advanced Medical Scientist-Programm 2019
Thema: "Funktion der Agonist-selektiven Rekrutierung von G Protein-gekoppelten Rezeptorkinasen für μ-Opioid-Rezeptor-vermittelte Wirkungen und Nebenwirkungen in vivo"
Zusammenfassung:
Morphin oder Fentanyl sind unverzichtbare Arzneistoffe in der Therapie starker Schmerzen (prä- und postoperativ in der Chirurgie, palliativ bei Tumorpatienten), deren therapeutische Anwendung durch z.T. lebensbedrohliche Nebenwirkungen stark eingeschränkt ist. Ziel des vorliegenden Projektantrages ist es, mit Hilfe neuer genetischer Mausmodelle Erkenntnisse über die Effektoren und die physiologischen Antworten der ß-Arrestin-gekoppelten Signalübertragung am μ-Opioid-Rezeptor und deren eindeutige Abgrenzung zu den G-Protein vermittelten Effekten zu gewinnen. Des Weiteren ist es Ziel, eine molekulare Erklärung für die Morphin-abhängige Suchtentstehung zu erhalten. Die Ergebnisse dieser Studie sind daher hochrelevant für die klinische Schmerztherapie sowie dem Verständnis der Entstehung von μ-Opioid-Rezeptor vermittelten Wirkungen und Nebenwirkungen bei der Behandlung von akuten und chronischen Schmerzzuständen.
Dr. Susanne Jahreis
Advanced Medical Scientist-Programm 2020
Thema: "MAIT-Zell assoziierte Immunantwort gegen Aspergillus fumigatus"
Zusammenfassung:
Invasive Pilzinfektionen, am häufigsten ausgelöst durch Fadenpilze der Gattung Aspergillus insbesondere Aspergillus fumigatus, sind eine der Hauptgründe für Mortalität bei HSCT Patienten. Ursächlich dafür ist eine stark gestörte primäre Immunabwehr, neueste Forschungsarbeiten zeigen zudem, dass MAIT-Zellen (Mucosal invariant associated T cells) bei HSCT Patienten in ihrer Funktionalität beeinträchtigt sind. Als T-Zellen mit einem invarianten T-Zellrezeptor besitzen MAIT-Zellen sowohl Eigenschaften der adaptiven als auch der angeborenen Immunität. Sie spielen eine Rolle bei der Abwehr von Bakterien und Viren, die Relevanz von MAIT-Zellen bei der Abwehr von Fadenpilzen ist jedoch noch unbekannt. Ziel dieses Projektes ist daher die Charakterisierung der Immunantwort von MAIT-Zellen gegenüber A. fumigatus durch Untersuchung 1) eines möglichen direkten zytotoxischen Effektes auf A. fumigatus und 2) des Verhaltens von MAIT-Zellen in einem in vivo-artigen Aspergillosis-on-chip Modell und 3) des Einflusses von MAIT-Zellen auf die Rekrutierung anderer Immunzellen im Biochip, sowie 4) der Funktion von MAIT-Zellen aus HSCT Patienten. Bestätigt sich die Schlüsselrolle von MAIT-Zellen bei der Abwehr von Pilzen, stellt dieser Zelltyp, einen neuen Ansatz für zelluläre Immuntherapien dar.
Dr. Tino Schenk
Advanced Medical Scientist-Programm
Thema: "Unlocking the curative potential of ATRA in non-APL AML: Identification of the mechanisms underlying repression of retinoic acid receptor activity by aberrant lysine modification."
Zusammenfassung:
The combination of a high median age at the time of diagnosis and a lack in targeted therapies makes acute myeloid leukemia (AML) one of the deadliest cancers. AML is characterized by a block in hematopoietic differentiation. One subtype of AML, acute promyelocytic leukemia (APL) can be cured using the retinoic acid receptor (RAR) agonist all-trans-retinoic acid (ATRA), enforcing myeloid differentiation. Non-APL AML cells are resistant to ATRA. This is at least in part due to downstream epigenetic deregulation. We found the lysine demethylase LSD1 and the acetyltransferase GCN5 to block ATRA induced differentiation in non-APL AML cells. Combination treatment with ATRA and inhibitors against LSD1 (GSK-LSD1) and GCN5 (MB3) triggered myeloid differentiation in AML cell lines and patients’ blasts. In this project we will analyze cells from a large cohort of patients aiming to identify cytogenetic, genetic and epigenetic factors that are responsible and therefore predictive for successful targeted treatment. Furthermore, we will investigate the in vivo effectiveness of MB3, the only available specific inhibitor of GCN5. To elucidate the interplay between RAR, LSD1 and GCN5 in AML we will map their chromatin binding sites and binding pattern changes using conventional and novel UV-Laser based chromatin immunoprecipitation technology. We believe that this project, combining translational and focused basic research, will greatly contribute to the development of therapies targeting the differentiation blockage in non-APL AML.
Prof. Dr. Adrian Press
Advanced Medical Scientist-Programm 2019
Thema: "Erforschung der Funktion von Proteinkinase C lsoformen in der Entstehung und Therapie der septischen Cholestase"
Zusammenfassung:
Eine exkretorische Leberdysfunktion ist die Folge verschiedenster Erkrankungen und in vielen, besonders in intensivmedizinischen Krankheitsbildern, mit Prognose und überleben assoziiert. Proteinkinase C (PKC) lsoformen regulieren, unterhalb von Phosphoinositid-3- Kinasen (Pl3K), in komplexen bis heute nicht vollständig erforschten molekularen Netzwerken, den kanalikulären Pol von Hepatozyten. Es wird vermutet, dass die PKCAktivierung in Hepatozyten ein maßgebliches Ereignis bei der Entstehung einer Cholestase ist. Bereits die pharmakologische und molekulare Inhibition von Pl3K-y konnte die septische Cholestase verhindern. Das Ziel des vorgeschlagenen Projektes ist es die für die Entstehung einer Cholestase relevanten PKC Klassen unterhalb der Pl3K-y zu identifizieren und zu erforschen, wie diese in einem präklinischen Modell der septischen Cholestase therapeutisch nutzbar gemacht werden können. Dafür stehen molekulare und funktionelle zelltyp-spezifische Untersuchungen in vitro und in vivo im Vordergrund, um Effekte der pharmakologischen PKC Inhibition auf die Hepatozyten-und lmmunzell-funktion zu untersuchen und dabei das Potential dieser Inhibitoren zur Therapie der Cholestase zu evaluieren.
Dr. Anja Urbach
Advanced Medical Scientist-Programm 2019
Thema: "Deciphering the developmenal origin and aging mechanisms of adult hippocampal neural stem cells through manipulation of cyclin D2"
Zusammenfassung:
Hippocampal neurogenesis is one of the most unique phenomena in the adult brain, as it continuously provides new neurons that confer an extraordinary degree of plasticity to the hippocampal circuitry, which is important for learning and memory. Perturbations of this process have been linked to neurological disorders and cognitive aging. Understanding how the generation of neurons from neural stem cells (NSCs) is controlled during development and aging is crucial to harness their therapeutic potential in regenerative medicine. Our previous studies suggest that cyclin D2 (D2) is critical for adult neurogenesis and for the establishment of the adult NSC population during postnatal development. In order to evaluate these findings with more precision, we have generated transgenic mice that allow the spatiotemporally controlled conditional deletion of D2. By using these mice in combination with in vivo lineage tracing and next generation sequencing, this project aims at validating the role of cyclin D2 for self-renewal and maintenance of the adult NSCs pool and to identify critical mechanisms of NSC aging. By extending these analyses to the postnatal period, this project further aims to elucidate the origin and the dynamic development of adult hippocampal NSC populations, which defines the initial amount of available NSCs and therefore the neurogenic potential throughout life.
Dr. Mei-Fang (Jasmine) Wu
Advanced Medical Scientist-Programm 2021
Thema: "The contribution of ceramides to cardiac injury"
Zusammenfassung:
Metabolic perturbations are the hallmarks of the failing heart. In the injured myocardium, accumulation of ceramides is observed. It is well-documented that inhibition of ceramide synthesis effectively lowers ceramide levels and rescues cardiac function. However, it remains inconclusive if accumulation of ceramides is sufficient to cause cardiac dysfunction in the absence of injury. In addition to metabolic disorder, disrupted protein homeostasis has also been reported in the injured myocardium. A recent study suggests that lipid metabolism coordinates protein homeostasis and that ceramides play critical role in regulating unfolded protein response. Nevertheless, their specific role in protein homeostasis in heart is not yet clear. Specific ceramide species that accumulate in the failing heart and coordinate the protein homeostasis response are the very-long-chain ceramides whose production is dependent on the ceramide synthase isoform 2 (cers2). Therefore, the goal of the project is to use a tetracycline-inducible Tet-on, cardiac-specific cers2 overexpression transgenic mouse model in combination with in vitro culture system to examine contribution of ceramide accumulation to cardiac damage and to delineate the link between ceramides and protein homeostasis.
Dr. Katja Franke
Advanced Medical Scientist-Programm 2020
Thema: "Region-specific BrainAGE in middle and late adulthood: Investigating the relationships between individual body, brain, and cognitive aging"
Zusammenfassung:
With life expectancy rising, it is important to determine what makes some people age more successfully than others. In particular, brain aging is associated with functional deterioration. However, this complex process is still poorly understood, with a likely contribution from individual health and lifestyle factors. In this proposal, I aim to extend the well-established global BrainAGE biomarker to a novel regional BrainAGE biomarker for individualized brain aging in order to systematically explore the complex relationships between individual brain aging, markers of physical aging and cognitive aging, i.e. determining which factors contribute to the individual differences between successful and unsuccessful aging in middle to late adulthood. This research project will use data on over 25,000 individuals. I will take a multi-faceted approach to define (i) structural brain aging, using region-specific BrainAGE scores, (ii) body aging, using a wealth of physiological and health data, and (iii) cognitive aging, using several standardized tests of cognitive function and ability, thereby creating three individual aging constructs. I expect that this research project will further elucidate the role of overall health for individual differences in brain aging.
Dr. Julia Reiche
Advanced Medical Scientist-Programm 2020
Thema: " Funktionelle Charakterisierung der Nexilin-Splicevarianten bei der Entwicklung von Tumoren und Kardiomyopathien"
Zusammenfassung:
Nexilin ist ein Protein, welches intrazellulär an den Z-Discs lokalisiert und in Muskelzellen verantwortlich scheint für die strukturelle Stabilität des Sarkomers unter mechanischer Belastung. Mutationen im Nexilin-Gen können dilatative oder hypertrophe Kardiomyopathien verursachen. Der zugrundeliegende Mechanismus ist bisher noch nicht bekannt. Wir konnten zeigen, dass (i) Nexilin in unterschiedlichen Splicevarianten in den Organen vorliegt, (ii) Nexilin - entgegen der bisherigen Literatur - auch in epithelialen Zellen exprimiert wird und, dass (iii) Nexilin das Adherens Junction-Protein E-Cadherin negativ reguliert und somit einen neuartigen Aspekt im Kontext der epithelialen Barriere und damit in der Tumorentwicklung und Metastasierung darstellt. Unser Forschungsprojekt hat zum Ziel die zugrundeliegenden Mechanismen zwischen Nexilin und E-Cadherin im Zusammenhang mit der Tumorbiologie genauer zu untersuchen. Unsere Arbeit soll aber auch zum besseren Verständnis der molekularen Ursachen von (Herz)Muskelschwächen beitragen.
Dr. Lejla Colic
Advanced Medical Scientist-Programm 2021
Thema: "Long-term consequences of early life trauma: multimodal imaging investigation of the underlying neurobiology in health and in mood disorders"
Zusammenfassung:
Early life trauma constitutes a major risk factor for mood psychopathology, and the effects on a eveloping brain have potent consequences on mental and physical health later in life. Individuals that have experienced early trauma, and later developed mood disorder, additionally have an increased risk for psychiatric and other comorbidities, such as trauma disorders, worsening of clinical course, and treatment resistance. This study proposes three complementary aims to investigate the effects of early trauma on the neurobiological and psychosocial architecture, clinical and diagnostic features in mood disorders, and treatment response to a novel ketamine medication. In the first aim, with the help of multimodal imaging, association between early life trauma, neurometabolites, connectivity and stress task will be investigated in healthy controls to establish a potential vulnerability for mood disorder development. In the second aim, individuals with mood disorders will undergo detailed imaging, diagnostic, and clinical phenotyping to investigate unique features of participants with both mood disorders and history of early trauma. Third aim will examine the effects of early trauma on treatment response to ketamine. Special attention will be given to gender as a moderating factor as it is strongly associated with prevalence rates of both early trauma and mood disorders.
Dr. Manuel Teichert
Advanced Medical Scientist-Programm 2021
Thema: "How senses work together: Cross-modal integration and plasticity in the adult mouse visual cortex"
Zusammenfassung:
Animals and humans constantly receive inputs from different sensory modalities simultaneously. While previous studies assumed that multiple sensory inputs converge only in higher association areas of the brain, recent studies provide evidence for multimodal merging already at the level of primary sensory cortices. However, how cross-modal inputs in primary sensory cortices modulate sensory processing of the main sense, and how they plastically adapt after sensory loss remains unknown. Here, we will address these issues by investigating the cross-modal effects of whisker-based tactile sensation on visual processing in the primary visual cortex (Vl) of adult mice before and after vision loss. Notably, our preliminary data indicate that whisker stimulation cross-modally suppresses visually driven Vl activity. We will further examine how tactile inputs affect important attributes of vision such as visual acuity, contrast sensitivity and orientation tuning in Vl. For this, we will use cutting-edge techniques such as in vivo intrinsic and two-photon imaging. To unravel the underlying anatomic pathways, we will perform retrograde and anterograde trans-synaptic anatomical tracing. These data will be analyzed by a novel algorithm based on deep learning for 3D detection of tracer-labeled cells. Finally, we will examine plastic changes in this cross-modal interplay after vision loss (VL) in vivo using again intrinsic and two-photon imaging . We assume that VL will induce a cross-modal functional recruitment of Vl by whisker-based tactile inputs. Our study will extend our understanding about cross-modal integration and will provide mechanistic insights into cross-modal plasticity after sensory loss in adult mice
Dr. Daniel Steinbach
Advanced Medical Scientist-Programm 2022
Thema: "Molekulare Mechanismen und Marker in der Karzinogenese und Progression des Harnblasenkarzinoms"
Zusammenfassung:
Das Harnblasenkarzinom gehört zu den häufigen altersassoziierten Tumoren und tritt primär, vorwiegend als nicht-muskelinvasiver Tumor auf. Häufige Rezidive sowie die Progression zum muskelinvasiven Tumor, einhergehend mit schlechter Prognose, und die invasive Diagnostik und Nachsorge sind eine große Herausforderung. Molekulare prognostische Marker und therapeutische Targets zur Vermeidung der Tumorprogression fehlen. In der Diagnostik sind invasive endoskopische Verfahren Standard und nicht-invasive Markern kaum etabliert. Durch genomweite Sequenzierung von Harnblasenkarzinomen und Urinsedimenten haben wir in den letzten Jahren mögliche Treiber der Progression sowie diagnostische Marker identifizieren können. Auf Basis dessen sollen in diesem Habilitationsprojekt:
(1) Die Rolle der durch Exom-Sequenzierung identifizierten progressions-assoziierten Gene MUC16, ACTG1, CHD8, IQGAP2 und THY1 sowie die Rolle des ß-Catenin Signalweges aufgeklärt werden.
(2) Die durch Sequenzierung des Methyloms der Urinsedimente von Harnblasenkarzinompatienten identifizierten nicht-invasiven Urinmarker in der Diagnose und Nachsorge des Harnblasenkarzinoms evaluiert werden.
Dr. Sathish Venkataramanappa
Advanced Medical Scientist-Programm 2022
Thema: "Role of DONSON in microcephaly and cortical development"
Zusammenfassung:
DONSON is an essential protein that, based on findings in cell lines, exerts multiple functions
in the cell cycle. Recently, biallelic mutations in the DONSON gene were linked to an extraordinary variety of clinically distinct phenotypes of microcephalic dwarfism. Yet, nothing is known about DONSON function in progenitor cells that establish the mammalian organism, and it remains elusive how distinct DONSON mutations cause such a wide spectrum of
clinical phenotypes. We examine DONSON function in mice, focusing on neural progenitors that establish the cerebral cortex. To circumvent early embryonic lethality of Donson-/- mice, we employ conditional Donson knockout mice and a Donson-/P472L model mimicking the DONSON gene defect discovered in two siblings with severe microcephaly in Jena. We will
test if the perturbed DONSON functions in our mouse models affects cell cycle progression, the ATR/ p53-mediated DNA damage response, and centrosome number. We bring to bear immunohistology, flow cytometry, ex utero and in utero electroporation, video microscopy, slice- and neurosphere-cultures, single nuclear RNAseq, and biochemical approaches. We
will significantly advance our understanding of DONSON function in endogenous progenitor cells and how DONSON mutations cause microcephaly and dwarfism.
Dr. Katrin Spengler
Advanced Medical Scientist-Programm 2023
Thema: "Carboxymethylierung von Tubulin in Endothelzellen und Konsequenzen für vaskuläre Dysfunktion und Alterung"
Zusammenfassung:
Mikrotubuli sind an der Regulation zahlreicher zellulärer Prozesse beteiligt. Ihre Bildung und Stabilität unterliegt einer komplexen Regulation durch posttranslationale Proteinmodifikationen. In eigenen Vorarbeiten konnte in humanen Endothelzellen gezeigt werden, dass eine Carboxymethylierung von Tubulin nach Einwirkung des Dicarbonyls Glyoxal die Polymerisierung von Tubulin hemmt. In der vorliegenden Studie soll untersucht werden, wie Carboxymethylierung die Mikrotubuli-Dynamik und die Interaktion von Mikrotubuli und assoziierten Regulator- und Motorproteinen in intakten Zellen beeinflusst und welche funktionellen Konsequenzen damit verbunden sind. Weiterhin soll der Einfluss der Carboxymethylierung auf den Acetylierungs-Code von Tubulin, insbesondere auf die Acetylierung am Lysin 40, welche die Stabilität der Mikrotubuli reguliert, geprüft werden. Eine dritte Frage bezieht sich auf den Nachweis von Tubulin-Carboxymethylierungen in pathophysiologisch relevanten Endothelzellmodellen, in denen endogen Dicarbonyle erhöht werden (Downregulation von Glyoxalase 1, Inkubation in Medium mit hoher Glukosekonzentration, Seneszenz). Diese Untersuchungen lassen neue Erkenntnisse zur Rolle der Mikrotubuli bei endothelialer Dysfunktion und Altern und zu präventiven Strategien erwarten.
Dr. Adriana Ruiz Rizzo
Advanced Medical Scientist-Programm 2022
Thema: "Brain connectivity underpinnings of visual attention dysfunctions in mild cognitive impairment"
Zusammenfassung:
The increasing aging rate in Western societies has rendered the early detection of dementia a top research priority. Older adults with mild cognitive impairment (MCI) show altered brain connectivity, which can signal a higher risk for dementia. However, altered brain connectivity in MCI is not well captured by current standard cognitive measures, thereby limiting the utility of
these measures for assessing disease detection and progression or treatment effectiveness in MCI. Although global memory problems are the most distinctive cognitive symptom in dementia, basic visual attention parameters have been found impaired in MCI. Hence, basic visual attention mechanisms could underlie some of the memory problems in MCI, such as in visual
scene memory. AttentionBrainConnect in MCI, ABC-MCI, will thus leverage an innovative task that includes mathematical modeling to investigate basic visual attention parameters, their association with brain connectivity, and their influence on visual scene memory in MCI. Specifically, parameters based on the theory of visual attention, brain connectivity based on
magnetic resonance imaging, and memory performance based on a scene memory recognition task will be obtained. Ultimately, ABC-MCI could yield neurocognitive markers for better disease detection and progression evaluation, and assessment of objective treatment effectiveness.
Dr. Andy Schumann
Advanced Medical Scientist-Programm 2023
Thema: "The relation of autonomic dysfunction and Post-COVID Fatigue: effect of autonomic biofeedback training"
Zusammenfassung:
More than 60% of people surviving COVID-19 infection suffer from persistent symptoms. When those symptoms last for at least 2 months in a period starting 3 months after the infection the term post-COVID-19 condition is used. Post-COVID-19 occurs in approximately 10%-14% of people infected, affecting over 5 million people. Debilitating fatigue is the most persistent and most prevalent symptom after COVID-19. As there is no established therapy, there is urgent need for research on potential interventions in patients with post-COVID-19 fatigue (PCF).
Excessive fatigue is generally accompanied by autonomic dysregulation that is characterized by sympathetic over-activation and withdrawal of parasympathetic influence on the heart. It has been suggested that autonomic dysfunction contributes to persistent fatigue by impairing cerebral blood flow. Thus, a training with a focus on enhancing cardiac parasympathetic control seems to be promising.
Our previous work suggests that HRV biofeedback increases parasympathetic modulation of heart rate and enhances prefrontal inhibitory control over limbic regions in the brain. These cortical structures play an important role in central regulation of cardiac activity but are also key regions in the so-called ‘fatigue network’. A functional brain network that was recently proposed. In patients with chronic fatigue syndrome, biofeedback of heart rate variability (HRV) has already been demonstrated to decrease fatigue levels. In this research proposal, we want to investigate the effect of HRV biofeedback on cardiac autonomic
regulation, fatigue levels and fronto-limbic connectivity in PCF patients. We hypothesize that an HRV increase after biofeedback will be accompanied by decreased subjective fatigue ratings. Data acquired in an inactive control group and a treatment-as-usual group will be used for comparison.