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Effects of Intracranial Pressure And 1-Carbon Metabolites on The Optic Nerve Sheath in VIIP Syndrome (First Award Fellowship)

Principal Investigator:
Julia Raykin, Ph.D.

Georgia Tech Research Corporation

Many astronauts experience visual impairment following long-term exposure to microgravity. One of the hypothesized mechanisms that leads to these ocular changes is remodeling of the optic nerve sheath due to increased intracranial pressures from exposure to microgravity. 1-carbon metabolites have been shown to be elevated in astronauts with VIIP and have been linked to pathological cardiovascular remodeling. The goal of this study is to develop an in vitro system to culture the optic nerve sheath under increased intracranial pressures and carbon-1 metabolites and monitor the cellular remodeling responses to these conditions. The results will give us a better understanding of the mechanisms involved in this condition and help identify possible interventions to prevent future visual decline in astronauts.

NASA Taskbook Entry

Technical Summary

Visual Impairment and Intracranial Pressure (VIIP) Syndrome is a loss in visual function that occurs in some astronauts following long-duration spaceflight. While the exact pathology of VIIP is not yet known, it is hypothesized that increases in intracranial pressure (ICP) drive optic nerve sheath (ONS) remodeling. Remodeling of the ONS can lead to changes in the normal function of the optic nerve which may in turn reduce visual acuity. In addition, recent evidence suggests that the development of VIIP is correlated with inter-individual variations in the 1-carbon metabolic pathway. These correlations are particularly intriguing because 1-carbon metabolism - and specifically buildup of the metabolite homocysteine - has been linked to pathologic vascular tissue remodeling, suggesting that variations in the 1-carbon pathway may have predisposed astronauts to the VIIP-promoting effects of increased ICP.

The primary objective of this work is to identify the anatomical changes that occur in the ONS in response to altered mechanical loading environments. In addition, this study aims to understand the role of 1-carbon metabolites in these adaptations. The central hypothesis of this work is that the cells of the ONS will remodel the extracellular matrix (ECM) in response to increased pressures and 1-carbon metabolites. In blood vessels, perturbations of stresses from their homeostatic values lead to cellular remodeling of the ECM. For example, in response to sustained increases in pressure, vascular cells synthesize ECM to thicken the vessel and reduce the local stresses on the cells. Therefore, it is hypothesized herein that the cells of the ONS respond similarly in response to increases in ICP.

In the proposed study we will (i) develop an ex vivo system to culture the porcine ONS under different mechanical loading conditions, (ii) characterize the synergistic effects of increased pressures and homocysteine levels on the remodeling of the ONS, and (iii) develop a computational model to describe the remodeling that occurs in response to altered mechanical loads and homocysteine levels. Typical tissue remodeling responses include synthesis of new ECM, increased protease production, and ECM reorganization, leading to changes in the material properties and altered function of the tissue. In the proposed work, these changes will be quantified by looking at collagen production, MMP expression, collagen microarchitecture, and the mechanical properties (stiffness and permeability) of the ONS in response to changes in ICP and homocysteine levels. Following the development of a predictive framework for the changes in the mechanical properties of the ONS, parametric studies will be used to test the effects of various factors on ONS remodeling. By integrating unique astronaut anatomical structures and biochemical profile, the model can become a powerful tool in predicting individualized spaceflight outcomes.

While data obtained from astronauts provides invaluable information on the effects of spaceflight on ophthalmic structures, ex vivo models are particularly useful for isolating the mechanisms specific to each contributing factor. Our major expected outcome is the development of a predictive framework for mechanical- and homocysteine-induced 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.

Earth Applications

The results of this research could be used to help patients suffering from increased intracranial pressure. The purpose of this work is to identify the remodeling responses to increased intracranial pressure in the optic nerve, which can help in identifying possible interventions to mitigate the effects of the increased pressure. In addition, 1-carbon metabolites may play an important role in the remodeling response of the optic nerve. Health care providers could monitor levels of 1-carbon metabolites to predict individual responses to raised intracranial pressure.