By Neal Lojek
The Francis College of Engineering, Department of Biomedical Engineering, invites you to attend a doctoral dissertation proposal defense by Neal M. Lojek on “A 3D hiPSC cortical tissue model for quantifying the effects of ionizing radiation on functional cortical networks.”
Candidate Name: Neal M. Lojek
Defense Date: Wednesday, March 29, 2023
Time: 9 to 10:45 a.m. EDT
Location: Perry Hall 111
Those interested in attending should contact Neal_Lojek@student.uml.edu and committee advisors, Chiara_Ghezzi@uml.edu or Bryan_Black@uml.edu at least 24 hours prior to the defense to request access to the meeting.
- Andrew Rogers, Associate Professor, Physics, University of Massachusetts Lowell
- Erno Sajo, Professor, Physics, University of Massachusetts Lowell
- Yanfen Li, Assistant Professor, Biomedical Engineering, University of Massachusetts Lowell
Brief Abstract: Studies on radiation induced injury have long been focused on hematopoietic, gastrointestinal, and cardiovascular systems; centered primarily on the relationship between DNA damage and subsequent cancers rather than the acute manifestations of disrupted cellular homeostasis. Currently, little is known about the acute or chronic effects of ionizing radiation (IR) on the function of human neuronal networks despite documented neurological symptoms accompanying radiation induced injury. The difficulty in studying this unique type of injury results from a lack of reliable experimental human neuronal tissue models. Thus, I propose to develop a 3D human cortical tissue model (CTM) for the purposes of studying effects of galactic cosmic radiation (GCR) exposure and screening potential pharmacological preventions and countermeasures.
The project will be carried out based on the following aims: (1) optimize and calibrate a 3D hiPSC-based CTM, (2) investigate the response of the CTM to proton beam exposure, and (3) compare the IR-induced biological response of low-energy protons and simulated GCR from the large Brookhaven National Laboratory accelerator to the CTM, with and without radioprotectant drugs. The CTM is composed of a 3D dense collagenous construct seeded with hiPSC-derived astrocytes and glutamatergic neurons, designed to mimic the morphological, mechanical, and biological properties of cortical tissue. The CTM allows for long term measurements of electrophysiological local field potentials (LFP) using microelectrode arrays (MEAs), giving a high-content readout of neuronal network activity. Additional biological readouts of the CTM include measurements of cell death, DNA damage, reactive oxygen species concentration, and transcriptional changes. Preliminary results demonstrate significantly increased cell death by lactate dehydrogenase assay (LDH), and nuclear staining for the DNA double-stranded break markers gH2AX, and 53BP1 as well as significantly reduced neurite length in CTMs exposed to 5 Gy of gamma radiation. Concomitantly, we observed significant inhibition of network level activity in 2D cortical co-cultures. In preliminary experiments, CTMs were treated with a known radioprotectant amifostine, demonstrating a reduction in IR-related biological effects. To further replicate the native cortical environment in the CTM, I will optimize the morphological, mechanical, and biological features of the construct by incorporating hyaluronic acid, a glycosaminoglycan native to brain extracellular matrix as well as other cortical tissue cell types, such as hiPSC-derived oligodendrocytes and microglia.
In addition, I will investigate the IR-induced biological response of low-energy protons and simulated GCR from the large Brookhaven National Laboratory accelerator to CTMs, as well as the effect of radioprotectant drugs on tissue function. In conclusion, the described CTM recapitulates essential elements of human cortical tissue (cell types, ECM composition, and neuronal network activity) and provides a novel tool for understanding mechanistic effects of IR-induced cortical injury as well as screening for new radioprotectant compounds to mitigate against radiation induced injury.