This grant studies the impact of variations in intracranial pressures (ICP) and 1-carbon metabolites on the development of Visual Impairment/Intracranial Pressure (VIIP) syndrome. Our specific objective is to identify the effects of ICP and 1-carbon metabolites on cellular remodeling in the optic nerve. Cellular remodeling has been implicated in many pathologies. Elucidation of the cellular mechanisms involved in VIIP will help identify possible interventions to treat/prevent the occurrence of VIIP. The overall project aims were to characterize the synergistic effects of increases in ICP and homocysteine on optic nerve sheath (ONS) remodeling. A key component of identifying the cellular response to these perturbations was to mechanically characterize the ONS as this tissue has not yet been mechanically described. One major impact of the cellular response to mechanical loading is the alteration of the extracellular matrix of the tissue. In order to identify the changes in these properties it was necessary to establish baseline values. We have determined that the optic nerve is under significant axial stretch in vivo, suggesting that current computational models might need to be altered to account for these stretches. In addition, we have been able to determine the axial and circumferential moduli of the optic nerve dura.

Another important finding from this work was that the addition of homocysteine to the culture medium of ONS led to an increase in the MMP expression in a dose dependent manner (MMP is an important indicator that remodeling is occurring). In addition, we have shown that mechanical stretch and homocysteine synergistically contribute to the remodeling response of ONS cells.

Progress: We have developed and characterized a mechanical testing/culture system to deliver pressure and axial load to the pig ONS. In addition, we have shown that the optic nerve is under significant axial tension in vivo. Our experiments indicate that mechanical loading and homocysteine synergistically stimulate remodeling of ONS cells and that homocysteine induces remodeling in the pig ONS in vitro.

This grant studies the impact of variations in intracranial pressures (ICP) and 1-carbon metabolites on the development of Visual Impairment/Intracranial Pressure (VIIP) syndrome. Our specific objective is to identify the effects of ICP and 1-carbon metabolites on cellular remodeling in the optic nerve. Cellular remodeling has been implicated in many pathologies. Elucidation of the cellular mechanisms involved in VIIP will help identify possible interventions to treat/prevent the occurrence of VIIP. The overall project aims were to characterize the synergistic effects of increases in ICP and homocysteine and to develop computational models to describe the remodeling that occurs in response in altered mechanical loading and homocysteine levels. A key component of identifying the cellular response to these perturbations was to mechanically characterize the (ON)/optic nerve sheath (ONS) as this tissue has not yet been mechanically described. One major impact of the cellular response to mechanical loading is the alteration of the extracellular matrix of the tissue. In order to identify the changes in these properties it was necessary to establish baseline values. We have determined that the optic nerve is under significant axial stretch in vivo, suggesting that current computational models might need to be altered to account for these stretches. In addition, we have been able to determine the axial and circumferential moduli of the optic nerve dura. The next step in this process will be to determine the effects of physiological changes on these mechanical properties.

Another important finding from this work was that the addition of homocysteine to the culture medium of ONS led to an increase in the MMP expression in a dose dependent manner (MMP is an important indicator that remodeling is occurring). These findings were ultimately important in order to push forward with the rest of the project. The characterization of the ONS will help us evaluate the effects of culturing the tissue under various conditions, which will help identify key factors in the development of VIIP. In addition, we have verified our hypothesis that homocysteine induces remodeling in the ONS.

In the coming year, we will perform more experiments with the addition of homocysteine to the cell culture medium to better understand homocysteine-induced remodeling mechanisms. We will simultaneously examine the effects of increased ICP. We expect that the synergistic effects of increased homocysteine levels and ICP will have a far greater impact on remodeling than either factor alone.

Visual Impairment/Intracranial Pressure (VIIP) syndrome refers to the loss in visual function that occurs in astronauts following long-duration spaceflights, accompanied by ophthalmic changes including optic disc edema, posterior globe flattening, choroidal folds, and distension and kinking of the optic nerve (ON)/optic nerve sheath (ONS). These changes tend to occur after a few weeks or months following exposure to microgravity. Many astronauts do not regain their preflight visual acuity, suggesting that permanent structural changes occur during spaceflight. While the exact causes are not yet known, it is hypothesized that increases in intracranial pressure (ICP) drive the remodeling (tissue reorganization or renovation) of the ONS, which leads to compression of the ON, ON compartmentation, altered cerebrospinal fluid (CSF) clearing and recycling and optic cell death resulting in reduced visual acuity. Recent evidence indicates that the development of VIIP is correlated with inter-individual variations in the 1-carbon metabolic pathway. The goal of this research is to elucidate the mechanisms that lead to the remodeling of optic nerve and develop a predictive model of these changes that can identify VIIP risk factors and possible interventions. This study will use a novel ex vivo ONS culture device to test the following hypotheses: i) Increased ICP induces remodeling of the ONS, ii) Increased concentrations of 1-carbon metabolites – specifically homocysteine – contribute to ONS remodeling, and iii) Increased ICP and homocysteine levels will have a synergistic effect on ONS remodeling. Our major expected outcome is the development of a predictive framework for ONS remodeling that can identify VIIP risk factors and possible interventions. The model can then be customized for each astronaut prior to spaceflight to predict individual microgravity-induced outcomes.