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Johns Hopkins Bloomberg School of Public HealthCAAT
 

CAAT Grants Program

Research Grants 2020-2021:

Summaries

  • Samantha Hughes, HAN University of Applied Sciences
    Resolving the Black Box: Using worms and TK/TD modeling to identify and characterize qAOP's
     
  • Jens Christian Schwamborn, University of Luxembourg
    Analysis of Parkinson's disease associated alpha-Synuclein aggregate toxicity in patient specific brain organdies
     
  • Emanuela Corsini, Universiti degli Studi di Milano (renewal)
    Understanding allergen potency: role of protein kinase C activation in the vigor of dendritic cell

Abstracts

Samantha Hughes, HAN University of Applied Sciences
Resolving the Black Box: Using worms and TK/TD modeling to identify and characterize qAOP's

The financial, ethical and scientific concerns associated with traditional animal testing have resulted in a shift towards alternatives that align to the 3R (Reduction, Replacement and Refinement)principle. The nematode Caenorhabditis elegansis well placed to reduce the number of animals used in toxicity testing, which currently amounts to over 1000 animals per year per chemical. C. eleganshave a similar genetic make-up and whole-body design (e.g. skin, intestine, neurones) to humans. Importantly, C. elegansare not subject to animal welfare acts. However, the potential of C. elegansto act within a strategy for regulatory toxicity testing is not yet fully realised.

Perfluorinated alkylated substances (PFAS) are man-made long carbon-chain chemicals with a variety of applications, including fire retardants, lubricants and pesticides. They are extremely resistant to degradation, and persist in the environment. Humans exposed to PFAS have significant health concerns, including altered fat metabolism, developmental toxicity and neurotoxicity. Shockingly, the link between PFAS exposure and its effects at the molecular and whole-body level remain elusive. “Resolving the black box” will explore how PFAS disrupts developmental and neurological processes, using C. elegans. The exposure concentrations of PFAS will be linked to biological effects using analytical chemistry methods, to generate toxicokinetic/toxicodynamic models. This will enable the quantification of Adverse Outcome Pathways (qAOPs) which will be used to design a battery of cell-based assays to assess the human relevance of the AOPs identified in C. elegans. Ultimately, “resolving the black box” will provide an invaluable contribution to strategies for chemical risk assessment.


Jens Christian Schwamborn, University of Luxembourg
Analysis of Parkinson's disease associated alpha-Synuclein aggregate toxicity in patient specific brain organdies

Parkinson's disease is a progressive neurological disorder. There are forms of the disease that are caused by changes in the genetic information (mutations), but for the majority of the cases we actually to not know the cause. Parkinson's disease has two major hallmarks, firstly the loss of a very specific group of nerve cells in the patients brain, these neurons produce the signal molecule Dopamine and hence are called dopaminergic neurons. The second hallmark is the appearance of aggregated proteins. In fact these aggregated proteins are believed to be problematic for the nerve cells and might cause their death. The aggregation of proteins might be caused by toxins which might come for the environment or even been produced by bacteria in the patients gut.

The aim of this project is to investigate how aggregated proteins might act toxic on dopamine producing nerve cells. In order to do that we use stem cells from Parkinson`s disease patients and treat them in a way that the differentiate into small three dimensional structures that share many features and characteristics with the actual human brain. Therefore these structures are often called mini-brains. Furthermore, we want to test new drug candidates that act against the potential toxic effect of aggregated proteins. We hope that on the long-range thereby we can provide evidence that it is possible to develop new medicatons by using these mini-brains as a cell culture model, so that eventually animal models can be replaced.

Emanuela Corsini, Universiti degli Studi di Milano (renewal)
Understanding allergen potency: role of protein kinase C activation in the vigor of dendritic cell

This project centered on the degree of dendritic cells activation/maturation following exposure to contact allergens of different potency and on the role of protein kinase C-β in dendritic cell activation/maturation. The challenge is to achieve a better understanding of the mechanisms that can explain the strength of allergic contact dermatitis reactions to weak, moderate, strong, and extreme sensitizers, and to develop a simple assay able to provide potency information, necessary for full replacement of animals in the assessment of the allergenic potential of chemicals. In the first year of the project, we identified in dendritic cells some critical parameters (i.e. HLA-DR and IL-12/IL-18) that can be used for the identification of extreme/strong sensitizers. During the second year, we confirmed the results using additional chemicals and the central role of protein kinase C in contact allergen-induced dendritic cell activation. In addition, to get further insights on allergen-induced dendritic cell activation, selected miRNAs were measured. Where, miRNAs are small non-coding RNA molecules known to regulate gene expression both transcriptionally and translationally, which in turn also regulate immune gene levels. A different modulation of miRNA was observed following exposure to contact allergens of different potency. Among the miRNAs investigated, miR-24-3p and miR-146a-5p are of particular interest for their role in T cell differentiation and allergic contact dermatitis. During the last year, the activities will centre on these selected miRNA. Their expression and function will be investigated in immature dendritic cells exposed to contact allergen of different potency.