Aim 1: To determine the effects of X-ray radiation on RAS, pro-oxidant and pro-fibrotic markers in the heart. The proposal hypothesizes that the combination of fish oil with pectin will mitigate radiation-induced pathology.

Aim 2: The impact of HZE (28Si, 48Ti) radiation on cardiac markers of pro-oxidant and pro-fibrotic signaling will be determined. This proposal postulates that intervention with fish oil and pectin will abrogate radiation-induced oxidative stress and fibrosis in the heart.

Aim 3: The effect of HZE (56Fe) radiation combined with X-Ray radiation at BNL will be determined on RAS, oxidative stress, pro-inflammatory markers, and pro-fibrotic signaling on heart. The proposal hypothesizes that deletion of a single p53 allele will significantly affect markers of oxidative stress, inflammation, and fibrosis.

The Multi-model Ensemble Risk Assessment project will develop an ensemble modeling approach for risk assessment where REID acceptance is determined based on the region of overlap between multiple predictive models allowing a straight forward method to input information derived from multiple sources including international risk prediction models.

Specific Aims:

Aim 1:  Determine mathematical formulism to implement multiple probabilistic and deterministic risk models into a single risk framework.

Aim 2: Identify common risk quantification parameters across cancer, cardiovascular disease, and late neurodegeneration consistent with Human System Risk Board quality of life consequences.

Aim 3: Develop visualization of results to support risk communication and decision making.

Aim 4: Develop multi-scale model for the evaluation of countermeasure efficacy based on human epidemiology and radiobiology data from NSRL.

Aim 5: Develop methodology to down select models for inclusion and retirement including appropriate weighting factors.

• Aim 1: Identify clinical characteristics, biofluid biomarkers and imaging features on baseline and follow-up multiparametric MRI that predict for cognitive decline following radiation exposure to the brain.
• Aim 2: Evaluate the relationship between changes in specific aspects of cognitive function with radiation dosimetry in the whole brain and brain subregions in patients receiving radiation to the brain.
• Aim 3: Identify early changes in multiparametric MRI measures that predict for subsequent changes in brain structure following radiation to the brain in preclinical and clinical studies.

• Aim 1: investigate late CNS/CVD Effects of Simplified 5-ion Mixed Field Beam (normalized to 500 mGy) GCR IRR in Male & Female AD Tg and WT Mice.

• Aim 2: investigate Late CNS/CVD Effects of Simplified 5-ion Mixed Field Beam IRR in Male and Female APP/E3 and APP/E4 Tg and WT Mice.

• Aim 3: investigate Acute and Late CNS and CVD Effects of Simplified 5-ion Mixed Field Beam Space Radiation on Human Cells In Vitro

Aim 1: Perform comprehensive evaluation of physiological and functional changes occurring in the     

murine cardiovascular system following exposure to different HZE radiation scenarios.  

Aim 2: Correlate cardiovascular functional changes with molecular pathway perturbations obtained from proteomic data sets (quantitative, dynamic and post translational modification).

AIM 1. Determine the longitudinal effect of IR type, dose and gender on cardiovascular physiology in wild type mice and isolated CV cells after single, low-dose, full-body proton (¹H), HZE particle iron (⁵⁶Fe) and mixed field and gamma radiation (? -IR).

AIM 2. Evaluate space-type IR mediated modulations in exosomal cargo in the blood, and determine whether these changes are associated with alterations in the heart function, structure and vasculature before manifestation of clinical symptoms.

AIM 3. Utilize known and newly identified biomarkers in the blood to develop human relevant point-of-care tests (POCT) for predicting and monitoring possible CV alterations before, during and after the space flights.

The objectives of this application are to characterize the impact of radiation doses and qualities on retinal vasculature and tissue remodeling and to study the role of mitochondria in regulating oxidative stress-induced cellular damage and alteration of cell-cell interactions in the function of blood-retina-barrier (BRB). Archived ocular tissues samples at dose ranges from 0.1 Gy to 1 Gy with multiple particle types and energies across multiple animal species will be available for sharing from three NASA funded investigators. We will evaluate radiation –induced retinal vascular and tissue remodeling at multiple time points. Our study will elucidate the spectrum of radiation-induced structural and functional alteration in retinal BRB function and the mechanisms by which these

changes are mediated.

Specific Aim 1:
Define the relationships between radiation-induced oxidative stress in ROS expression, retinal vascular remodeling, and BRB function. We will correlate cellular oxidative status with changes in retinal vascular topology, vascular endothelial cells (ECs), and BRB integrity using immunohistochemistry (IHC), stereological and automated image analyses, and magnetic resonance imaging diffusion tensor imaging (DTI-MRI). The observed changes in mice will be compared with that of rats and rabbits.

Specific Aim 2:
Determine whether radiation-induced oxidative damage in retina is mediated through photoreceptor mitochondrial ROS production. We will examine mitochondrial associated-oxidative stress and apoptosis and mitochondrial integrity in retinal photoreceptor using Western blot assays and histopathology.

Aim 1. To compare and contrast the efficacy of countermeasures to High-LET exposure

in cultured heart cells.

Aim 2: Compare and contrast the efficacy of druggable molecules in the long-term

management in an animal model of high-LET radiation induced cardiomyopathy.

• AIM 1: Discovery and validation of miRNAs biomarkers that are altered as a function HZE exposure, at a dose that could result in increased cardiovascular risks in astronauts on long duration space mission.

• AIM 2: Discovery and validation of miRNAs and lncRNAs altered as a function of exposure to 0.2 Gy Silicon ions in C3H mice and matched sham controls.

Aim 1. Establish temporal profiles of human telomere length dynamics (before, during, and

after flight) for individual astronauts across the integrated One-Year Mission Project onboard the

ISS, and across the concurrent ground analog component (prolonged isolation missions).

• Evaluate telomere length dynamics (qRT-PCR) and shifts in individual telomere length distributions (Telo-FISH); bulk vs. stem/early progenitor cell populations

• Evaluate telomerase status/expression (TERT and HIF-1a protein levels; ELISA)

Aim 2. Establish temporal profiles of DNA damage responses (before, during, and after flight)

for individual astronauts across the integrated One-Year Mission Project onboard the ISS, and

across the concurrent ground analog component (prolonged isolation missions).

• Evaluate DNA damage responses; genomic vs. telomeric (g-H2AX foci, TIFs)

• Evaluate cytogenetic damage/biodosimetry; genome instability, telomere-specific oxidative damage, and ALT activation (Telo-dGH/G-rich sister telomere loss/T-SCE)

GSAM project provides delivery scheme of low and high LET particles to best simulate 600/900 day Mars missions within facility and animal constraints.

• Studies required to inform countermeasure testing and validation
• Fluence based versus acute exposures to simulate space radiation 

GSAM (GCR Simulation and Mitigation) research objectives:

Aim 1:  Design and implement Hybrid Shield Concept to simulate GCR environment at NSRL to include production of secondaries and correlated multiplicities found in space

Aim 2:  Validate ground simulation of dose rate including fractionation and time course delivery of particles to simulate low dose chronic exposures in space.  

Aim 3: Evaluation of dose delivery scheme with biological timescales to inform chronic studies.

Aim 4: Expand design and implement Mars surface simulation at NSRL to include mixed field environment found on Mars surface.

• Aim 1: Identify radiation-induced alterations in the bone marrow, focusing on myeloid cell inflammatory changes associated with aging and how these contribute to endothelial and immune system dysfunction as well as propensity for clonal hematopoiesis.
  
  
• Aim 2: Identify similar effects in CNS myeloid cells (microglia) and their contribution to synaptic loss and cognitive dysfunction.
  
  
• Aim 3: Identify potential intersection between systemic immune and CNS effects.

Dose-rate and mixed field animal and cellular studies, supporting the development and concept of operations of the NSRL GCR Simulator, are sought to:

Specific Aims:

• Aim 1: Provide data to define the dose delivery scheme for low-LET radiation, the dose delivery scheme for high-LET radiation, and the time course (duration) of cellular and animal studies for simulation of GCR-induced endpoints; including studies to understand the principles governing biological responses to a mixed field of low- and high-LET radiation.

• Aim 2: Reduce uncertainties in dose-rate effects used to estimate risks from space radiation exposures.

Secondary aim:

• Aim 3: Generate mixed field RBEs for relevant endpoints.

• Specific Aim A: To facilitate the integration of space radiobiology research results into improved models of BR radiation risk projections.
• Specific Aim B: To complete the cancer risk uncertainty analysis factors to be used for near-term mission planning (trade studies), and to update these as new radiobiological data sets become available.
• Specific Aim C: To develop descriptive and predictive models of modifications to biochemical pathways known likely to be causative of cancer risk.
• Specific Aim D: To integrate or develop new data and models of DNA damage, transmissible chromosomal aberration including translocation, insertions, terminal deletion including telomere loss, and other aberrations related to chromosomal instability or cancer initiation, incorporating applications to the simulations in Specific Aim C.
• Specific Aim E: To perform a comprehensive assessment of available acute radiation risk projection models, and to develop simulation software of acute risk for mission design assessments.