The Need for Biological Countermeasures to Mitigate the Risk of Space Radiation-Induced Carcinogenesis, Cardiovascular Disease, and Central Nervous System Deficiencies.

NASA's currently planned long-duration, deep space exploration missions outside of low Earth orbit (LEO) will result in the exposure of astronauts to relatively high lifetime doses of ionizing radiation (IR), exceeding what humans have previously encountered in space. Of concern to this exposure are the long-term health consequences of radiation carcinogenesis, cardiovascular and degenerative disease, and central nervous system decrements. Existing engineering solutions are insufficient to decrease the lifetime accumulated IR exposure to levels currently allowable by agency standards, therefore appropriate countermeasure and mitigation strategies must be developed to enable long duration missions. Emerging discoveries in the fields of radiation oncology and the mitigation of Acute Radiation Syndrome (ARS) have demonstrated the potential for compound-based/biological radiomodifiers to drastically improve clinical outcomes and represent a promising strategy for space radiation countermeasure development. This review outlines the unique challenges posed by the space radiation environment, defines the limits of terrestrial radiation protection strategies in space, describes a brief overview of current space radiation countermeasure development strategies, highlights potential new approaches for countermeasure identification and development, and speculates on the potential benefits beyond space exploration.

Utilizing microphysiological systems and induced pluripotent stem cells for disease modeling: a case study for blood brain barrier research in a pharmaceutical setting.

Microphysiological systems (MPS) may be able to provide the pharmaceutical industry models that can reflect human physiological responses to improve drug discovery and translational outcomes. With lack of efficacy being the primary cause for drug attrition, developing MPS disease models would help researchers identify novel targets, study mechanisms in more physiologically-relevant depth, screen for novel biomarkers and test/optimize various therapeutics (small molecules, nanoparticles and biologics). Furthermore, with advances in inducible pluripotent stem cell technology (iPSC), pharmaceutical companies can access cells from patients to help recreate specific disease phenotypes in MPS platforms. Combining iPSC and MPS technologies will contribute to our understanding of the complexities of neurodegenerative diseases and of the blood brain barrier (BBB) leading to development of enhanced therapeutics.

Facilitating the commercialization and use of organ platforms generated by the microphysiological systems (Tissue Chip) program through public-private partnerships.

Microphysiological systems (organs-on-chips, tissue chips) are devices designed to recapitulate human physiology that could be used to better understand drug responses not easily addressed using other in vivo systems or in vitro animal models. Although still in development, initial results seem promising as tissue chips exhibit in vivo systems-like functional responses. The National Center for Advancing Translation Science (NCATS) identifies this technology as a potential tool that could improve the process of getting safer, more effective treatments to patients, and has led to the Tissue Chip Program, which aims to develop, integrate and validate major organ systems for testing. In addition to organ chip development, NCATS emphasizes disseminating the technology to researchers. Commercialization has become an important issue, reflecting the difficulty of translation from discovery to adoption and wide availability. Therefore, NCATS issued a Request for Information (RFI) targeted to existing partnerships for commercializing tissue chips. The goal was to identify successes, failures and the best practices that could provide useful guidance for future partnerships aiming to make tissue chip technology widely available.

Microbiome remodelling leads to inhibition of intestinal farnesoid X receptor signalling and decreased obesity.

The antioxidant tempol reduces obesity in mice. Here we show that tempol alters the gut microbiome by preferentially reducing the genus Lactobacillus and its bile salt hydrolase (BSH) activity leading to the accumulation of intestinal tauro-ß-muricholic acid (T-ß-MCA). T-ß-MCA is an farnesoid X receptor (FXR) nuclear receptor antagonist, which is involved in the regulation of bile acid, lipid and glucose metabolism. Its increased levels during tempol treatment inhibit FXR signalling in the intestine. High-fat diet-fed intestine-specific Fxr-null (Fxr(ΔIE)) mice show lower diet-induced obesity, similar to tempol-treated wild-type mice. Further, tempol treatment does not decrease weight gain in Fxr(ΔIE) mice, suggesting that the intestinal FXR mediates the anti-obesity effects of tempol. These studies demonstrate a biochemical link between the microbiome, nuclear receptor signalling and metabolic disorders, and suggest that inhibition of FXR in the intestine could be a target for anti-obesity drugs.

The National Institutes of Health Microphysiological Systems Program focuses on a critical challenge in the drug discovery pipeline.

The National Institutes of Health has partnered with the US Food and Drug Administration and the Defense Advanced Research Projects Agency to accelerate the development of human microphysiological systems (MPS) that address challenges faced in predictive toxicity assessment and efficacy analysis of new molecular entities during the preclinical phase of drug development. Use of human MPS could provide better models for predicting the efficacy of new molecular entities in clinical trials. It is also anticipated that improvements in predicting drug toxicities early in the drug development process through the use of MPS or human organs-on-a-chip will decrease the need to withdraw new therapies from the market and minimize or eliminate deaths due to unidentified drug toxicities.

The effects of resveratrol and selected metabolites on the radiation and antioxidant response.

Excess reactive oxygen species (ROS) generated from ionizing radiation (IR) or endogenous sources like cellular respiration and inflammation produce cytotoxic effects that can lead to carcinogenesis. Resveratrol (RSV), a polyphenol with antioxidant and anticarcinogenic capabilities, has shown promise as a potential radiation modifier. The present study focuses on examining the effects of RSV or RSV metabolites as a radiation modifier in normal tissue. RSV or a RSV metabolite, piceatannol (PIC) did not protect human lung fibroblasts (1522) from the radiation-induced cell killing. Likewise, neither RSV nor PIC afforded protection against lethal total body IR in C3H mice. Additional research has shown protection in cells against hydrogen peroxide when treated with RSV. Therefore, clonogenic survival was measured in 1522 cells with RSV and RSV metabolites. Only the RSV derivative, piceatannol (PIC), showed protection against hydrogen peroxide mediated cytotoxicity; whereas, RSV enhanced hydrogen peroxide sensitivity at a 50 µM concentration; the remaining metabolites evaluated had little to no effect on survival. PIC also showed enhancement to peroxide exposure at a higher concentration (150 µM). A potential mechanism for RSV-induced sensitivity to peroxides could be its ability to block 1522 cells in the S-phase, which is most sensitive to hydrogen peroxide treatment. In addition, both RSV and PIC can be oxidized to phenoxyl radicals and quinones, which may exert cytotoxic effects. These cytotoxic effects were abolished when HBED, a metal chelator, was added. Taken together RSV and many of its metabolic derivatives are not effective as chemical radioprotectors and should not be considered for clinical use.

Murine Prkdc polymorphisms impact DNA-PKcs function.

Polymorphic variants of DNA repair genes can increase the carcinogenic potential of exposure to ionizing radiation. Two single nucleotide polymorphisms (SNPs) in Prkdc, the gene encoding the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), have been identified in BALB/c mice and linked to reduced DNA-PKcs activity and mammary cancer susceptibility. We examined three additional mouse strains to better define the roles of the BALB/c Prkdc SNPs (R2140C and M3844V). One is a congenic strain (C.B6) that has the C57BL/6 Prkdc allele on a BALB/c background, and the other is a congenic strain (B6.C) that has the BALB/c variant Prkdc allele on a C57BL/6 background. We also examined the LEWES mouse strain, which possesses only one of the BALB/c Prkdc SNPs (M3844V). Our results demonstrate that both Prkdc SNPs are responsible for deficient DNA-PKcs protein expression, DNA repair and telomere function, while the LEWES SNP affects only DNA-PKcs expression and repair capacity. These studies provide insight into the separation of function between the two BALB/c SNPs as well as direct evidence that SNPs positioned within Prkdc can significantly influence DNA-PKcs function involving DNA repair capacity, telomere end-capping, and potentially cancer susceptibility.