Advanced Medical Scientist-Programm 2025

Thema: "Entwicklung theranostischer Radiopharmaka für die Behandlung von Hepatozellulärem Karzinom"

Zusammenfassung:
Im Rahmen der AMSP-Förderung des IZKF sollen potenzielle Radio-Theranostika (d.h. Radiopharmaka für Diagnostik und Therapie) für die Behandlung des Hepatozellulären Karzinoms (HCC) entwickelt werden. Diese würden ein patienten-individuelles, nicht-invasives Staging der Erkrankung und die Beurteilung der Leberfunktion sowie der Therapierbarkeit des Tumors mit der einer internen Bestrahlung des HCCs mit tumoriziden Beta-Minus-Teilchen (Radionuklidtherapie) kombinierbar machen. Hierfür sollen HCC-spezifische Farbstoff-basierte Radiopharmaka durch „Markierung“ mit radioaktiven Iod-Isotopen entwickelt werden, mit dem Fluoreszenzfarbstoff Indocyaningrün (ICG) als Leitstruktur, da dieser in vielen HCCs gespeichert wird. Die hepatobiliäre Clearance und die HCC-Speichercharakteristik der Radiopharmaka wird präklinisch anhand eines HCC-Xenograft-Modells unter Verwendung bebrüteter Vogeleier als Tierversuchsersatzmodell
durchgeführt. Am Ende des Projektes soll die Translation des best perfoming Theranostikums an einem ersten klinischen Einzelfall erreicht sein. Die AMSP-Förderung soll zur Finanzierung einer Doktorandin sowie zur Deckung von Sachkosten verwendet werden und dabei die Durchführung des Vorhabens, die Habilitation der Antragstellerin sowie den Aufbau einer unabhängigen Nachwuchsforschergruppe unter Leitung der Antragstellerin ermöglichen.

Advanced Medical Scientist-Programm 2025

Thema: "Characteristic macrophages in glioblastomas"

Zusammenfassung:
Glioblastomas (GBM) are one of the most aggressive primary brain tumors in adults. Despite various strategies including differential single cell gene expression analyses between GBM and healthy tissues, none of the resulting findings could benefit the development of promising therapies, yet. Various macrophage populations coevolve in the tumor microenvironment of GBMs and not only support a tumor immune evasion but also tumor spreading throughout the surrounding tissue, ultimately resulting an incomplete resectability with very high recidive frequencies. We could identify a Siglec10+CX3CR1+ macrophage population, which was specific to GBMs when compared to other very frequent tumor entities like meningiomas (MNGs), non-GBM gliomas and metastases (MTS).
In our project, we will characterize this potentially pro-tumorigenic Siglec10+CX3CR1+ macrophage population on transcriptome level, test its capacity to modulate tumor and immune cells in their microenvironment, describe their generation in presence of GBM tumor cells and analyze metabolic alterations in their local, residential microenvironment. Our goal is to distillate unique markers or interaction mechanisms as targets for new promising therapies. Modulation of these macrophages could stop the diffuse growth of GBMs and potentially would result in a total resectability of GBMs without recurrence.

Advanced Medical Scientist Programm 2024

Thema: ETAR in ovarian carcinoma: Modulation of signaling activity by kinases and phosphatases

Zusammenfassung:
The G protein coupled receptor (GPCR) endothelin receptor type A (ETAR) was found to be an important player in many different cancer types, among them ovarian carcinoma. Specific GPCR kinases (GRKs) phosphorylate the receptor and initiate its
desensitization via β-arrestins. One of the GRKs, GRK5 was reported to be significantly downregulated in ovarian cancer patient samples. In initial studies, we identified GRK5 as the most important GRK in regulating β-arrestin recruitment and ETAR trafficking. Therefore, we will investigate the influence of GRK5 on the ETAR signaling and the malignancy of ovarian carcinoma. The dephosphorylation by phosphatases (PPs) is in general understudied in the GPCR field, despite its crucial
role in resensitization of the receptor. We plan to identify the phosphatases acting on the ETAR and will create KO cell lines to further study their part in mediating the malignant potential of the ovarian carcinoma cell line A2780. The molecular insights
that will be gained in this project will open the possibility to identify novel treatment strategies for this hard to treat cancer type.

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.

Advanced Medical Scientist-Programm 2023

Thema: "The neurotrophic cytokine GDF15 - a potential epigenetic target for modulating orthodontic pain?"

Zusammenfassung:
During orthodontic therapy, 94 % of patients experiencing considerable pain with peaks around 24 hours after each treatment procedure. This should be considered critically, since it significantly affects the patient motivation and commitment to undergo and continue orthodontic therapy. Pharmacological treatment of orthodontic pain commonly targets the inflammatory component of nociceptor nerve activation. Unfortunately, this appears to be detrimental to tooth movement by impacting tissue and bone remodeling. These processes are triggered by a local aseptic inflammation modulated by periodontal ligament fibroblasts. We recently reported that GDF15, a TGF-β superfamily member, contributes to their mechanoresponse and in general agreement with other studies, our preliminary results also suggest a neurotropic role in the orthodontic context. Being discussed as potential intervention target in a variety of medical conditions, epigenetically adapting GDF15 levels by modulating histone modifications are considered as promising approach. However, with regard to orthodontics, the role of GDF15 in pain perception has not yet been addressed. Therefore, this study aims to investigate the neurotropic properties and underlying mechanisms of GDF15 in the context of orthodontic pain perception in vitro and in vivo, further focusing on the role of epigenetic regulation and a potential therapeutic inhibitor application.

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.

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.

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.

Voraussetzung. Sie können einen Antrag auf Förderung stellen, wenn

• Sie wissenschaftlicher Mitarbeiter/wissenschaftliche Mitarbeiterin der Medizinischen Fakultät der FSU Jena sind,
• Ihre Promotion nicht länger als 9 Jahre zurückliegt (Elternzeiten, die in diesen Zeitraum fallen, werden angerechnet (pro Kind 2 Jahre)) und Sie noch nicht habilitiert sind,
• Sie einen Gesamt-Impaktfaktor > 40 erreicht haben und dabei mindestens eine Originalpublikation mit Impaktfaktor > 6 als Erst- oder Letztautor vorweisen können (bei Publikationen als Erst- oder Letztautor in für das jeweilige Fachgebiet herausragenden Journalen
  kann in Absprache mit dem IZKF-Vorstand der notwendige Gesamt-Impaktfaktor niedriger sein),
• Sie eine Habilitation in einem klinischen oder experimentellen Fach beabsichtigen und dies durch entsprechende Vorarbeiten belegen können,
• eine Stellungnahme der verantwortlichen Instituts- oder Klinikleitung vorliegt, dass Ihre Stelle für den beantragten Förderzeitraum gesichert ist.

Das Programm hat eine Laufzeit von drei Jahren mit einer Zwischenbegutachtung nach 2 Jahren. Der Förderumfang beträgt bis zu 50.000 € pro Projekt und Jahr für Sach- und Personalmittel, wobei auch bis zu 50 % der eigenen Stelle finanziert werden kann. Der nächst-vorgesehene Förderzeitraum ist der 01.09.2025 bis 31.08.2028 (nach positiver Zwischenevaluation).

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

• Ausschreibung
• AMSP-Vorlage Bewerbungsunterlagen
• AMSP_Formblatt Stellungnahme Einrichtungsleitung
• AMSP_Formblatt Bestätigung wissenschaftler Einrichtung
• AMSP_Formblatt Bereitschaftserklärung Antragstellende