Space radiation-induced bystander signaling in 2D and 3D skin tissue models

Thesis (Sc. D.)--Harvard-MIT Program in Health Sciences and Technology, 2012.Page 157 blank. Cataloged from PDF version of thesis.Includes bibliographical references (p. 145-156).Space radiation poses a significant hazard to astronauts on long-duration missions, and the low fluences of charged particles characteristic of this field suggest that bystander effects, the phenomenon in which a greater number of cells exhibit damage than expected based on the number of cells traversed by radiation, could be significant contributors to overall cell damage. The purpose of this thesis was to investigate bystander effects due to signaling between different cell types cultured within 2D and 3D tissue architectures. 2D bystander signaling was investigated using a transwell insert system in which normal human fibroblasts (A) and keratinocytes (K) were irradiated with 1 GeV/n protons or iron ions at the NASA Space Radiation Laboratory using doses from either 2 Gy (protons) or 1 Gy (iron ions) down to spacerelevant low fluences. Medium-mediated bystander responses were investigated using three cell signaling combinations. Bystander signaling was also investigated in a 3D model by developing tissue constructs consisting of fibroblasts embedded in a collagen matrix with a keratinocyte epidermal layer. Bystander experiments were conducted by splitting each construct in half and exposing half to radiation then placing the other half in direct contact with the irradiated tissue on a transwell insert. Cell damage was evaluated primarily as formation of foci of the DNA repair-related protein 53BP1. In the 2D system, both protons and iron ions yielded a strong dose dependence for the induction of 53BP1 in irradiated cells, while the magnitudes and time courses of bystander responses were dependent on radiation quality. Furthermore, bystander effects were present in all three cell signaling combinations even at the low proton particle fluences used, suggesting the potential importance of including these effects in cancer risk models for low-dose space radiation exposures. Cells cultured in the 3D constructs exhibited a significant reduction in the percentages of both direct and bystander cells positive for 53BP1 foci, although the qualitative kinetics of DNA damage and repair were similar to those observed in 2D. These results provide evidence that the microenvironment significantly influences intercellular signaling and that cells may be more radioresistant in 3D compared to 2D systems.by Sarah B. Lumpkins.Sc.D

Enabling Space Exploration Medical System Development Using a Tool Ecosystem

The NASA Human Research Program's (HRP) Exploration Medical Capability (ExMC) Element is utilizing a Model Based Systems Engineering (MBSE) approach to enhance the development of systems engineering products that will be used to advance medical system designs for exploration missions beyond Low Earth Orbit. In support of future missions, the team is capturing content such as system behaviors, functional decompositions, architecture, system requirements and interfaces, and recommendations for clinical capabilities and resources in Systems Modeling Language (SysML) models. As these products mature, SysML models provide a way for ExMC to capture relationships among the various products, which includes supporting more integrated and multi-faceted views of future medical systems. In addition to using SysML models, HRP and ExMC are developing supplementary tools to support two key functions: 1) prioritizing current and future research activities for exploration missions in an objective manner; and 2) enabling risk-informed and evidence-based trade space analysis for future space vehicles, missions, and systems. This paper will discuss the long-term HRP and ExMC vision for the larger ecosystem of tools, which include dynamic Probabilistic Risk Assessment (PRA) capabilities, additional SysML models, a database of system component options, and data visualizations. It also includes a review of an initial Pilot Project focused on enabling medical system trade studies utilizing data that is coordinated across tools for consistent outputs (e.g., mission risk metrics that are associated with medical system mass values and medical conditions addressed). This first Pilot Project demonstrated successful operating procedures and integration across tools. Finally, the paper will also cover a second Pilot Project that utilizes tool enhancements such as medical system optimization capabilities, post-processing, and visualization of generated data for subject matter expert review, and increased integration amongst the tools themselves

The NASA Twins Study: A multidimensional analysis of a year-long human spaceflight

To understand the health impact of long-duration spaceflight, one identical twin astronaut was monitored before, during, and after a 1-year mission onboard the International Space Station; his twin served as a genetically matched ground control. Longitudinal assessments identified spaceflight-specific changes, including decreased body mass, telomere elongation, genome instability, carotid artery distension and increased intima-media thickness, altered ocular structure, transcriptional and metabolic changes, DNA methylation changes in immune and oxidative stress-related pathways, gastrointestinal microbiota alterations, and some cognitive decline postflight. Although average telomere length, global gene expression, and microbiome changes returned to near preflight levels within 6 months after return to Earth, increased numbers of short telomeres were observed and expression of some genes was still disrupted. These multiomic, molecular, physiological, and behavioral datasets provide a valuable roadmap of the putative health risks for future human spaceflight