Team:TAS Taipei/Model
Model
Cataract prevention occurs over 20 – 50 years, so we cannot perform experiments on the long-term impact of adding GSR or CH25H. However, computational biology allows us to predict cataract development in the long-term. These models allow our team to understand the impact of adding GSR-loaded nanoparticles into the lens over a 50 year period, and to design a full treatment plan on how to prevent and treat cataracts with our project. Therefore, the results of our model are essential in developing a functional prototype.
For sake of clarity, we will discuss each model in detail with respect to prevention (using GSR) only. At the end, we explain these results to treatment. In addition, we include collapsibles for interested readers and judges, in order to fully document our modeling work (eg. assumptions, mathematics) while keeping the main page clear with basic points only.
Introduction
- How much GSR to maintain in the lens?
- How to maintain that amount of GSR using nanoparticles and eyedrops?
Focus of Models
Since our construct is not directly placed into the eyes, how our synthesized protein impacts the eye after it is separately transported into the lens is of greater importance. As a result, we create models with the intent on understanding how GSR and CH25H impacts the eye.
Relation to Experiments
We use measurements from the cataract lens experiment to create the first model, and extend the results with the second model to find GSR concentrations, which our experiments could not find.
We modelled nanoparticle degradation before performing actual experiments, to estimate the optimal amount of protein to load into the nanoparticles. After performing the experiments, we can directly compare them to see the efficiency of our drug-loading. Although we could not experimentally test an eyedrop prototype, model 4 extends the results of the nanoparticle degradation to better understand how to use eyedrops to deliver nanoparticles.
Relation to Overall Project
Although experiments could validate a prototype, it is through modeling that we find the optimal designs for these prototypes. By building a full calculator, we can envision how the results of this project can be applied clinically. A patient finds his or her LOCS score from the physician, and then enters it into the calculator, which returns a full treatment plan, using standardized cataract prevention and treatment eyedrops. Our nanoparticles are fully customizable, to allow physicians to alter the design to best fit a patient’s specific cataract conditions.
Model 1: Crystallin Damage
The amount of damage to crystallin by H2O2 determines the severity of a cataract. We relate the amount of crystallin damage to the corresponding rating on the LOCS scale, used by physicians to rate cataract severity. Our goal is to lower LOCS to below 2.5, the threshold for surgery. Through literature research as well as our own experimental data, we find the maximum allowable crystallin damage to prevent a LOCS 2.5 cataract from developing.
Measurement of Cataract Severity
There are four ways of measuring cataract severity, each used for a different purpose.
- Lens Optical Cataract Scale (LOCS): Physicians use this scale, from 0 – 6, to grade the severity of cataracts.
- Absorbance at 397.5 nm: This is the experimental method, used by our team in the lab (c.d.)
- Crystallin Damage: This is a chemical definition. We quantify cataract severity as a function of how much oxidizing agents there are, as well as how long crystalline is exposed to oxidizing agents.
Measurement of Cataract Severity
Numerous studies show how absorbance measurements can be converted to the LOC scale that physicians use. With the results of ________ and ________, we construct the first two columns in Table 2.
Absorbance Equivalence to Crystallin Damage: Experimental Data
We use experimental data from our team’s Cataract Lens Model (link). They induced an amount of crystallin damage, and measured the resulting absorbance. With this relation in Figure 2, we calculate the equivalent crystallin damage of each LOCS rating and absorbance.
Conclusion
To guarantee that surgery is not needed for 50 years, we need to limit crystallin damage to 0.9981 units. If crystallin damage goes above this threshold, then surgery is needed. This is the crystallin damage threshold for a LOCS 2.5 cataract.
Model 2: GSR Pathway
Now that we know how much GSR we need to limit crystallin damage to LOCS 2.5, we model the naturally occurring GSR Pathway in the lens of a human eye. For prevention (2A), we calculate the necessary GSR concentration to be maintained over 50 years so that the resulting cataract is below LOCS 2.5.
Chemical Kinetics Model: Differential Equations
By the Law of Mass Action, Michaelis-Menten Enzyme kinetics, Ping-pong mechanism, and the Law of Passive Diffusion, we build a system of 10 differential equations based on 6 chemical reactions. All parameters, constants, and initial conditions are based off literature data. Estimates made are also shown with assumptions and reasoning. The details are shown in the collapsible for interested readers.
Blackbox Approach: Testing GSR Impact
We vary the input, Initial GSR concentration, holding all other variables constant, and numerically solve for the amount of hydrogen peroxide over time. With this graph, we can find the amount of crystallin damage accumulated over 20 to 50 years if different levels of GSR is maintained.
From this graph, we can find the GSR concentration needed for the LOCS 2.5 threshold and the LOCS 1.0 threshold.
Crystallin Damage vs. GSR Level
According to literature data and our model, the naturally occurring GSR concentration is 10 uM. All curves show crystallin damage decreasing as GSR levels are increased, which supports both research and experimental data, and suggests that this prototype is effective in preventing crystallin damage. However, GSR levels need to be raised significantly, up to 40+ uM from the natural 10 uM of GSR in order to show long-term protection.
Table 3 shows the amount of GSR we need to maintain for 50 years in order to prevent a LOCS cataract of a certain severity. The row of interest is LOCS 2.5, the threshold for surgery. Notice that we say “maintain” the level of GSR. This level needs to be constant at all times for 50 years for full prevention. The delivery of GSR to maintain this level is discussed in Model 3.
Conclusion
We need to maintain (NOT add) 43.5 uM of GSR in the lens so that the crystallin damage recorded over 50 years is below the LOCS 2.5 threshold.
Citations
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