Medical Scientist-Programm 2024

Thema: "Molecular characterization of the effects and side effects of the pan-somatostatin analog pasireotide"

Zusammenfassung:
Early detection of malignant tumors and their targeted treatment remains a major challenge for oncologists. Receptors for regulatory peptide hormones can be expressed at considerable densities on certain human tumors. To date, the five G protein-coupled receptors for somatostatin (SST1-SST5) have been prototypes for the development of such targeted therapies. In fact, overexpression of SST receptors is the molecular basis for the use of stable somatostatin analogs such as octreotide (SST2) and pasireotide (SST1, SST2, SST3, SST5) in the diagnosis and treatment of neuroendocrine tumors. Although pasireotide displays superior therapeutic effects compared to octreotide, its clinical use is limited by serious side effects such as induction of hyperglycemia by an unknown molecular mechanism. Therefore, a systematic analysis of the pharmacological target structure(s) of pan-somatostatin analogs is urgently needed. We have developed a humanized SST5 knockin mouse and an SST5 knockout mouse line. These mouse models will enable us to analyze which effects of pasireotide and other pan-somatostatin analogs are mediated via the SST5 receptor. In particular, these studies should show whether the known action profile of pasireotide is typical for all pan-somatostatin analogs or whether it is possible to develop pan-somatostatin analogs with fewer side effects.

Medical Scientist-Programm 2024

Thema: "Molecular mechanisms underlying dendritic spine recovery after ischemic stroke"

Zusammenfassung:

Regaining of neurophysiological functions in peri-infarct areas (the penumbra) and remapping
processes in functionally related cortical tissues are thought to represent important aspects
underlying recovery from stroke in human patients. However, such processes are far from being
understood at the cellular and molecular level. We have recently uncovered that ischemic stroke
causes damages in dendritic arborization in peri-infarct areas, which then are repaired by
processes of dendritic regrowth relying on the actin nucleator Cobl. We will follow our exciting
working hypothesis that also the powerful poststroke recovery process for dendritic spines in periinfarct
areas after ischemic stroke relies on the function of proteins important for actin filament
formation. In detail, we aim to uncover the role of Cobl in dendritic spine recovery after ischemic
stroke and the importance of further MCAO-regulated actin nucleation promoting factors – JMY,
Spire 2 and Cobl-like - for dendritic spines. We expect that our comprehensive studies will unravel
molecular mechanisms underlying the powerful poststroke recovery process for dendritic spines
in peri-infarct areas after ischemic stroke. Our studies will provide new insights into whether actin
nucleation promoting factors may hold some beneficial potential in neuroprotection and in
regeneration processes by structural and functional reorganizations in the brain.

Medical Scientist-Programm 2023

Thema: "The dynamic brain in anorexia nervosa: uncovering novel neurobiological mechanisms and opportunities for new therapies"

Zusammenfassung:
The brain dynamically uses stable configurations of neuronal connection to integrate, coordinate, and initiate adaptive behaviours in response to internal and external stimuli. Thanks to advanced magnetic resonance imaging (MRI) techniques and state-of-art methodologies, investigation of such functional brain configurations, or states, is now possible, offering new insights into brain alterations underlying mental disorders. Current anorexia nervosa research has not yet made use of those advances, limiting the understanding of neurobiological mechanisms that underlay the disease. This research proposal aims to shed some light for the first time on dynamic brain changes occurring over different stages of the disease. Specifically, we aim to quantify disrupted dynamics, identify microstructural abnormalities with novel technologies and methods, and establish links between them and disorder-defining symptoms and behaviours. Overall, brain functional dynamic analysis could provide novel insights into the system-level disruptions underlying anorexia nervosa, which may lead to a better understanding of the disorder and, eventually, might deliver diagnostic or prognostic indicators.

Medical Scientist-Programm 2023

Thema: "What is the developmental relevance of sleep-related spontaneous brain activity?"

Zusammenfassung:
Sleep is believed to play a fundamental role in brain development but its functional and structural implications that could lead to neurological and psychological disorders when sleep is deprived during brain development is not yet understood. Within the current project we will develop and establish a mouse model with sleep deprivation during a critical period of brain development. The underlying changes in spontaneous network activity will be recorded with wide-field Ca2+ imaging and local field potential recording. Functional and structural changes after long-term sleep deprivation will be investigated by means of imaging techniques and behavioral tests. Preterm infants in the neonatal intensive care unit are often disturbed while sleeping. Therefore, we are aiming at establishing a method to continuously monitoring sleep states in preterm infants. This will allow us to implement a clustered care regime based on individual sleep states of the patients to improve their sleep on the neonatal intensive care unit. If a continuous sleep state classification for preterm infants was possible we could not only study the longterm improvement in the prevalence of neurological and psychological disorders when sleep conditions were improved, but also other various developmental trajectories in relation to the infants sleep.

Medical Scientist-Programm 2023

Thema: "The Unfolded Protein Response as a protective mechanism In Sepsis—TUPRIS"

Zusammenfassung:
Sepsis describes a common elusive medical syndrome that was redefined as a combination of infection that is associated with organ dysfunction. The molecular processes leading to organ dysfunction in septic patients are still poorly understood. Animal studies from others and us indicate that expression of genes regulating cellular metabolism are essential for the maintenance of organ function. Preliminary data leading to this proposal shows that polymicrobial sepsis induces a hypometabolic response, which could have an important impact by reducing disease severity during sepsis. However, the underlying mechanism leading to hypometabolism during sepsis is still unclear. The hypothesis of TUPRIS is that the Unfolded Protein Response (UPR) is as a protective mechanism in sepsis and underlies sepsis-associated hypometabolism. For this, I will perform complementary gain- and loss-of function approaches in mice of different genotypes subjected to a polymicrobial sepsis and subsequential secondary infection. I expect that by blocking activation of the UPR, mice will fail to induce hypometabolism during sepsis increasing disease severity. The results from this project will reveal how metabolic adaptation is achieved during severe systemic infections and shall identify the UPR as an attractive therapeutic target.

Medical Scientist-Programm 2022

Thema: "Impact of altered ER homeostasis on Golgi structure and function"

Zusammenfassung:
Many genes encoding structural components of the endoplasmic reticulum (ER), such as ARL6IP1 or FAM134B mutations, are associated with neurodegenerative disorders. Both FAM134B and ARL6IP1 are ER resident proteins, which play a major role for ER structure and ER turnover. Because the ER and the Golgi apparatus are closely interdependent and because of our preliminary data on FAM134B, we here hypothesize that a compromised ER structure can impact on the structure and function of the Golgi apparatus. So far, little attention has been paid to this connection. Therefore, we propose to study the consequences of disruption of the ER proteins FAM134B and ARL6IP1 on Golgi structure, function and the Golgi stress response. Moreover, we will assess whether ER stress inhibitors have an effect on Golgi structure and function.

Medical Scientist-Programm 2022

Thema: "Ziel ist es, die Rolle von proinfllammatorischen Ceramiden und vor allem der Ceramidsynthase 2 (CerS2) bei der Doxorubicin- vermittelten Kardiomyopathie zu untersuchen."

Zusammenfassung:
Tod durch Herzversagen gehört immer noch zu den häufigsten Todesursachen der industrialisierten Welt und weitere Forschungen sind immer noch notwendig, um die genaue Progression zu verstehen und neue Behandlungsmethoden zu entwickeln. Eine Variante der Entwicklung einer Kardiomyopathie sind Nebenwirkung anderer Medikamente, wie z.B. Doxorubicin (Dox). Dox ist ein Anthracyclin und wird vor allem zur Behandlung von Krebs eingesetzt. Eine charakteristische Nebenwirkung von Dox ist die Kardiotoxizität, dessen Ursachen noch immer nicht vollständig geklärt sind. Es ist u.a. bekannt, dass Dox langkettige und sehr langkettige Ceramide erhöht, welche jedoch größtenteils als weiterer Nebeneffekt des Medikaments angesehen wird. Ceramide sind spezielle Fette und als solche in verschiedene Signalwege involviert. Eine Akkumulation von proinflammatorischen langkettigen und sehr langkettigen Ceramiden steht im Zusammenhang mit Mitochondrienschädigung und Zelltod. Ziel dieses Forschungsprojektes ist es, eine Korrelation und Kausalität zwischen spezifisch erhöhten Ceramiden und den kardiotoxischen Effekten von Doxorubicin nachzuweisen und zu verifizieren. Dazu werden sowohl in vitro als auch in vivo Methoden eingesetzt.

Medical Scientist-Programm 2022

Thema: "Entwicklung metallbasierter Diagnostika für die bildgebende Leberdiagnostik mittels PET/CT und MRT"

Zusammenfassung:
Die Antragstellerin hat radioaktive Gallium-68-Komplexe entwickelt, welche in präklinischen Versuchen eine vielversprechend hohe Leberspezifität und biliäre Exkretion aufwiesen. Somit besitzen diese Verbindungen dezidiertes Potential, als Radiodiagnostika (sog. „Tracer“) in der Positronen-Emissions-Tomographie (PET) eingesetzt zu werden und zeitlich und räumlich hochaufgelöste Darstellungen der Leber zu erzeugen. Solche PET-Tracer würden eine Alternative zur leberspezifischen MRT darstellen – aktuell das bildgebende Standardverfahren in der Leberdiagnostik – welche einerseits hinsichtlich bestimmter Patientengruppen anwendungslimitiert und andererseits durch den Einsatz schwermetallhaltiger Kontrastmittel (KM) risikobehaftet ist. Durch die IZKF-Förderung sollen mehrere Drittmittelprojekte sowie auch Kooperationen mit der regionalen Pharmaindustrie ermöglicht werden. Diese translational ausgerichteten Projekte beabsichtigen die chemische Modifikation der entwickelten Komplexe mit dem Ziel einer optimierten Pharmakokinetik, die präklinische Evaluation und den Transfer in die pharmazeutische Produktion. Hierbei sollen sowohl Gallium-68 als auch Eisen(III) als signalgebende Metalle verwendet werden, um Leberbildgebung sowohl mit PET-Tracern als auch mit MRT- Kontrastmitteln betreiben zu können.

Medical Scientist-Programm 2022

Thema: "To assess risk profiles and protective factors in the development of neurodegenerative disease in patients with chronic insomnia, and to understand their underlying pathomechanisms"

Zusammenfassung:
Chronic Primary Insomnia (CPI) affects 6-10% of the adult population and predisposes patients to a 1.5 to 1.55-fold higher risk of developing Alzheimer’s Dementia (AD) in later life, making early identification of at-risk patients critical. However, this is difficult, as insomnia is a heterogeneous clinical symptom culminating in different insomnia phenotypes. This project therefore aims to assess whether different insomnia phenotypes are associated with different neurodegenerative risk profiles. Furthermore, the exact pathomechanisms underlying this neurodegenerative process are not clear. On the one hand, hyperarousal, which plays a prominent role in the aetiology of insomnia, leads to over activity of the stress axes, namely sympathetic over-activity and glucocorticoid excess, thereby accelerating neuronal loss and cerebral deposition of amyloid β. On the other hand, loss of slow-wave sleep, another hallmark of insomnia, downregulates glymphatic system activity in animal models, which lowers extracellular drainage capacity, thus leading to a build-up of amyloid β. Thus, the second objective is to uncover which pathomechanism underlies the neurodegenerative processes seen in CPI patients. Finally, some aspects of healthy sleep revealed by intact sleep microarchitecture, such as spindle density, cyclic alternating patterns, and amount of Rapid Eye Movement (REM) sleep, play a protective role in cognitive decline in healthy, older adults. The third aim of this study is thus to explore whether intact sleep microarchitecture also plays a protective role in cognitive decline in CPI.

Medical Scientist-Programm 2021

Thema: "This project deals with the emerging role of astrocytes during brain structural plasticity."

Zusammenfassung:
The project aims to elucidate the mechanisms which mediate the rewiring of our brain during challenging tasks. For yet unknown reasons, these processes are non-invasively detectable by using structural magnetic resonance imaging (MRI) and manifest as grey matter expansions in task-relevant areas which renormalize with increasing success. We translated the human approach into an animal model (monocular deprivation, MD) and our preliminary data suggest transient swelling of astrocytes as main driver leading grey matter to expand. In order to appropriately examine this novel finding, we now switch to the molecular level and want to generate a comprehensive signature of the astrocytic translatome which will provide valuable explanatory approaches regarding their involvement in the rewiring of neuronal circuits. As core experiment we use our previous MD model which enables the comparison of different plasticity patterns in different areas of the brain. A dedicated transgenic approach thereby will allow both, the extraction of the translatome and the imaging of sparsely labeled cells. We thus elucidate neuronal plasticity from the astrocytic side which might emerge as a valid therapeutic target to boost the function of diseased or aging brains.

Sie können sich mit Ihrem Projekt für das Medical Scientist-Programm bewerben, wenn Sie:

• wissenschaftliche Mitarbeiterin/wissenschaftlicher Mitarbeiter des Universitätsklinikums Jena sind, Ihre Promotion nicht länger als 6 Jahre zurückliegt (Mutterschutz- und Elternzeiten, die in diesen Zeitraum fallen, werden pro Kind mit 2 Jahren angerechnet) und Sie noch nicht habilitiert sind,
• einen Gesamt-Impact-Faktor >15 erreicht haben und dabei mindestens eine Publikation mit IF >4 als Erst- oder Letztautorenschaft vorweisen können,
• das ausdrückliche Ziel verfolgen, einen Antrag auf Drittmittelförderung (DFG, BMBF, EU oder vergleichbare Förderinstitution) einzureichen und für das geplante Forschungsvorhaben entsprechend Aussicht auf Erfolg besteht,
• nötige Vorarbeiten zur erfolgreichen Beantragung eines solchen Drittmittelprojektes im Rahmen der hier vorliegenden Fördermaßnahme durchführen wollen,
• nicht bereits eine Juniorprojektförderung des IZKF erhalten haben,
• nicht bereits als Antragstellender (Projektförderung) von der DFG, dem BMBF, der EU oder einer gleichwertigen Fördereinrichtung gefördert worden sind,
• vorweisen können, dass Ihre Stelle in der jeweiligen Einrichtung über den beantragten Förderzeitraum hinaus als Voraussetzung für eine Drittmitteleinwerbung gesichert ist.  

Die Programmlaufzeit beträgt 3 Jahre mit einer Zwischenevaluation nach 2 Jahren. Der Förderumfang beträgt bis zu 38.000 € pro Projekt und Jahr für Sachmittel und Personalmittel. Im Einzelfall ist eine Mitfinanzierung der eigenen Stelle des Antragstellenden bis zu 50 % oder die Beantragung von Stellenanteilen für technische Assistenz möglich. Der letzte vorgesehene Förderzeitraum ist der 01.04.2024 bis 31.03.2027 (nach positiver Zwischenevaluation). 

Folgende Dokumente stehen für die Antragserstellung für Sie zum Downloaden zur Verfügung:

• Ausschreibung
• MSP_Vorlage Bewerbungsunterlagen 
• MSP_Formblatt Stellungnahme Leitung
• MSP_Formblatt Bestätigung  wissenschaftliche Gasteinrichtung
• MSP_Formblatt Bereitschaftserklärung Antragstellende