A5021958718- Virus-based gene therapy research
- Barrier Structure and Function Studies
- RNA Interference and Gene Delivery
- Neuroinflammation and Neurodegeneration Mechanisms
- Pulmonary Hypertension Research and Treatments
- RNA regulation and disease
- Alzheimer's disease research and treatments
- Angiogenesis and VEGF in Cancer
- Lysosomal Storage Disorders Research
- Viral Infectious Diseases and Gene Expression in Insects
- Viral Infections and Immunology Research
- Vascular Malformations Diagnosis and Treatment
- Intracerebral and Subarachnoid Hemorrhage Research
- CRISPR and Genetic Engineering
- Neurological Disease Mechanisms and Treatments
- Adenosine and Purinergic Signaling
- Child Nutrition and Feeding Issues
- Axon Guidance and Neuronal Signaling
- Infant Nutrition and Health
- Long-Term Effects of COVID-19
- Zebrafish Biomedical Research Applications
- Thyroid Disorders and Treatments
- Immunotherapy and Immune Responses
- Macrophage Migration Inhibitory Factor
- Viral gastroenteritis research and epidemiology
Universität Hamburg
2015-2025
University Medical Center Hamburg-Eppendorf
2015-2025
University Cancer Center Hamburg
2015-2024
University of Lübeck
2019-2022
University Medical Center
2021
University Hospital and Clinics
2021
Abstract Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in of patients with COVID-19 elucidate potential mechanisms underlying the vascular pathology. In brains severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals animal models, found an increased number empty basement membrane tubes, so-called string representing remnants lost capillaries. We obtained evidence that brain...
Gene therapy critically relies on vectors that combine high transduction efficiency with a degree of target specificity and can be administered through safe intravenous route. The lack suitable vectors, especially for gene brain disorders, represents major obstacle. Therefore, we applied an in vivo screening system random ligand libraries displayed adeno-associated viral capsids to select brain-targeted the treatment neurovascular diseases. We identified capsid variant showing unprecedented...
Hypertension is a leading cause of stroke and dementia, effects attributed to disrupting delivery blood flow the brain. also alters blood-brain barrier (BBB), critical component brain health. Although endothelial cells are ultimately responsible for BBB, development maintenance properties depend on interaction with other vascular-associated cells. However, it remains unclear if BBB disruption in hypertension requires cooperative Perivascular macrophages (PVM), innate immune closely...
The low-density lipoprotein receptor–related protein 1 (LRP1) is an endocytic and cell signaling transmembrane protein. Endothelial LRP1 clears proteinaceous toxins at the blood–brain barrier (BBB), regulates angiogenesis, increasingly reduced in Alzheimer’s disease associated with BBB breakdown neurodegeneration. Whether loss of endothelial plays a direct causative role neurodegenerative changes remains elusive. Here, we show that inactivation from mouse endothelium results progressive...
A limiting factor for the use of adeno-associated viruses (AAVs) as vectors in gene therapy is broad tropism AAV serotypes, i.e., parallel infection several cell types. Nanobodies are single immunoglobulin variable domains from heavy chain antibodies that naturally occur camelids. Their small size and high solubility allow easy reformatting into fusion proteins. Herein we show a membrane protein-specific nanobody can be inserted surface loop VP1 capsid protein AAV2. Using three structurally...
Vectors mediating strong, durable, and tissue-specific transgene expression are mandatory for safe effective gene therapy. In settings requiring systemic vector administration, the availability of suited vectors is extremely limited. Here, we present a strategy to select with true specificity target tissue from random peptide libraries displayed on adeno-associated virus (AAV) by screening library under circulation conditions in murine model. Guiding vivo next-generation sequencing, were...
Rationale: In pulmonary arterial hypertension (PAH), endothelial dysfunction and obliterative vascular disease are associated with DNA damage impaired signaling of BMPR2 (bone morphogenetic protein type 2 receptor) via two downstream transcription factors, PPARγ (peroxisome proliferator-activated receptor gamma), p53. Objective: We investigated the vasculoprotective regenerative potential a newly identified PPARγ-p53 factor complex in endothelium. Methods Results: this study, we...
Brain arteriovenous malformations (bAVMs) are a leading cause of hemorrhagic stroke and neurological deficits in children young adults, however, no pharmacological intervention is available to treat these patients. Although more than 95% bAVMs sporadic without family history, the pathogenesis largely unknown, which may account for lack therapeutic options. KRAS mutations frequently observed cancer, recent unprecedented finding human offers new direction bAVM research. Using novel...
Abnormal angiogenesis and regression of the diseased retinal vasculature are key processes associated with ischemic retinopathies, but underlying mechanisms that regulate vascular remodeling remain poorly understood. Here, we confirmed specific expression semaphorin 3G (Sema3G) in endothelial cells (ECs), which was required for amelioration retinopathy. We found Sema3G elevated vitreous fluid patients proliferative diabetic retinopathy (PDR) neovascularization phase oxygen-induced (OIR)....
Symptoms often persistent for more than 4 weeks after COVID-19-now commonly referred to as 'Long COVID'. Independent of initial disease severity or pathological pulmonary functions tests, fatigue, exertional intolerance and dyspnea are among the most common COVID-19 sequelae. We hypothesized that respiratory muscle dysfunction might be prevalent in persistently symptomatic patients with self-reported exercise intolerance.In a small cross-sectional pilot study (n = 67) mild-to-moderate...
A genetic deficiency of the solute carrier monocarboxylate transporter 8 (MCT8), termed Allan-Herndon-Dudley syndrome, is an important cause X-linked intellectual and motor disability. MCT8 transports thyroid hormones across cell membranes. While hormone analogues improve peripheral changes deficiency, no treatment neurological symptoms available so far. Therefore, we tested a gene replacement therapy in Mct8- Oatp1c1-deficient mice as well-established model disease. Here, report that...
Abstract Blood-brain barrier (BBB) breakdown and immune cell infiltration into the central nervous system (CNS) are early hallmarks of multiple sclerosis (MS). High numbers CD8 + T cells found in MS lesions, antigen (Ag) presentation at BBB has been proposed to promote entry CNS. Here, we show that brain endothelial process cross-present Ag, leading effector differentiation. Under physiological flow vitro, Ag prevented crawling diapedesis resulting apoptosis breakdown. Brain vivo was limited...
Abstract The human Alzheimer’s disease (AD) brain accumulates angiogenic markers but paradoxically, the cerebral microvasculature is reduced around Aß plaques. Here we demonstrate that angiogenesis started near plaques in both AD mouse models and samples. However, endothelial cells express molecular signature of non-productive (NPA) accumulate, plaques, a tip cell marker IB4 reactive vascular anomalies with NOTCH activity. Notably, NPA induction by loss presenilin, whose mutations cause...
Abstract Cerebral cavernous malformations (CCMs) and spinal cord (SCCMs) are common vascular abnormalities of the CNS that can lead to seizure, haemorrhage other neurological deficits. Approximately 85% patients present with sporadic (versus congenital) CCMs. Somatic mutations in MAP3K3 PIK3CA were recently reported CCM, yet it remains unknown whether mutation is sufficient induce Here we analysed whole-exome sequencing data for CCM found ∼40% them have a single, specific [c.1323C>G...
Adeno-associated virus (AAV) is a promising in vivo gene delivery platform showing advantages delivering therapeutic molecules to difficult or undruggable cells. However, natural AAV serotypes have insufficient transduction specificity and efficiency kidney Here, we developed an evolution-directed selection protocol for renal glomeruli identified what believe be new vector termed AAV2-GEC that specifically efficiently targets the glomerular endothelial cells (GEC) after systemic...
Pathological high shear stress (HSS, 100 dyn/cm
Vascular pathology is associated with cognitive impairment in diseases such as type 1 diabetes; however, how capillary flow affected and the underlying mechanisms remain elusive. Here we show that capillaries diabetic mouse brain both sexes are prone to stalling, blocks consisting primarily of erythrocytes branches off ascending venules. Screening for circulating inflammatory cytokines revealed persistently high levels interleukin-10 (IL-10) mice. Contrary expectation, stimulating IL-10...