Multi-scale model of the mammalian lower urinary tract to study function and dysfunction, and to design/optimize stimulation techniques

Investigators
Dr. Satish S. Nair, Dr. David J. Schulz, Dr. Ilker Ozden, Dr. Yi Zhang
Contact info (email)
nairs@missouri.edu
1. Define context(s)
identify/explore new therapies
other
Current Conformance Level / Target Conformance Level
Extensive
Primary goal of the model/tool/database

Network models for the lower urinary tract (LUT) are not publicly available presently to guide the development and optimization of components of the neural lower urinary tract in mammals. 

Although research has helped shed light on the functioning of specific components of the neural LUT in mammals, and of the effect of neuromodulation on specific dysfunction, the dynamics of the linkages among the various components of the LUT circuit and how they coordinate function during normal and injury cases remains unclear. There is need for a fully functional biophysical network model integrating the key components of the LUT for understanding function and for designing stimulation techniques to alleviate dysfunction. A key requirement is that the model provide testable predictions. For design of stimulation techniques, we will focus on developing capability to permit users to both (i) optimize existing strategies, and (ii) aid in the design of improved neuromodulation therapy for bladder dysfunction. We will develop sand-box models of both components and of the overall network to provide the user to both generate 'what if' scenarios of interest to them, and to simulate those scenarios to generate testable predictions related to functioning, dysfunction, and therapy. To guide the user, we will provide well-documented example cases.

Biological domain of the model
lower urinary tract (LUT) of mammals
Structure(s) of interest in the model
neural circuit of LUT, dynamic model of bladder, bladder afferents and efferents
Spatial scales included in the model
10^-6 to 10^-2 meters
Time scales included in the model
10^-4 to 10^2 seconds
Other uses for the model (optional)

The sand-box models of component and overall network models will also be very useful for training researchers and device development teams about (i) the normal functioning of the lower urinary tract system, and (ii) the effect of neuromodulation therapies such as open- and closed-loop electrical stimulation, and pharmacological interventions to alleviate dysfunction.  In addition, the material can be incorporated into undergraduate and graduate courses such as physiology, neuroscience, bioengineering, device development, and computational neuroscience, at both graduate, undergraduate and K-12 levels. At Univ of Missouri, we plan to incorporate this as a 'case study' into undergraduate and graduate computational neuroscience course that the PI teaches, and into neural engineering lessons that he is developing for K-12.

2. Data for building and validating the model
Data for building the model Published? Private? How is credibility checked? Current Conformance Level / Target Conformance Level
in vitro (primary cells cell, lines, etc.) Yes Extensive
ex vivo (excised tissues)
in vivo pre-clinical (lower-level organism or small animal) Yes Adequate
in vivo pre-clinical (large animal)
Human subjects/clinical
Other: ________________________
Data for validating the model Published? Private? How is credibility checked? Current Conformance Level / Target Conformance Level
in vitro (primary cells cell, lines, etc.) Yes Adequate
ex vivo (excised tissues)
in vivo pre-clinical (lower-level organism or small animal)
in vivo pre-clinical (large animal)
Human subjects/clinical
Other: ________________________
3. Validate within context(s)
Who does it? When does it happen? How is it done? Current Conformance Level / Target Conformance Level
Verification On-line session held every six months for independent verification by users Continuous by the developers. Every six months by independent users. We will conduct on-line session sessions for independent users by providing them with access to models hosted at our Lab server. Interested users will be provide free accounts so they can test out the versions at the site and provide feedback Extensive
Validation Developers and Users will perform independent evaluation Through out the model development process Again, on-line sessions will be provided for independent users. They will be provided with access to models hosted at our Lab server. Extensive
Uncertainty quantification One of the central goals of the model is to quantify the role of uncertainty in component and network parameters, all of which impact the network outputs Through out the development process Since this is one of the key objectives of the project, all developers explicitly design the model providing options for uncertainty in parameters Adequate
Sensitivity analysis The model GUI will have buttons to permit users to perform sensitivity analysis. Results from such analysis will be provided in the documentation for the key parameters, one at a time. Users can try other combinations. For each new case We will provide a tool to perform such an analysis automatically, once the user selects the parameter of interest Adequate
Other:__________
Additional Comments
4. Limitations
Disclaimer statement (explain key limitations) Who needs to know about this disclaimer? How is this disclaimer shared with that audience? Current Conformance Level / Target Conformance Level
Mouse; But will provide models for cat and human using limited data presently available Researchers and Clinicians Models for mouse, cat and humans will be provided, but highlighting that data are only beginning to come in for cat and human Extensive
5. Version control
Current Conformance Level / Target Conformance Level
Extensive
Naming Conventions? Repository? Code Review?
individual modeler Yes Yes
within the lab NA
collaborators NA Yes
6. Documentation
Current Conformance Level / Target Conformance Level
Code commented? Extensive. Code commenting will follow normal guidelines. We have uploaded several models in NEURON to the ModelDB database of Yale/Duke
Scope and intended use described? Extensive. All documentation will have this.
User’s guide? Extensive. Every model will have detailed user's guide, as well as YouTube tutorials
Developer’s guide? Extensive. All documentation above will also highlight how the users can modify and/or use their own code for any component in the network model. Examples of all such scenarios will be provided, as appropriate, including using YouTube tutorials.
7. Dissemination
Current Conformance Level / Target Conformance Level
Extensive
Target Audience(s): “Inner circle” Scientific community Public
Simulations
Models Free access to all models for interested users via our server and for download via a GitHub site Free access to all models for interested users via our server and for download via a GitHub site
Software Interested users can download from a GitHub site Interested users can download from a GitHub site
Results Publications and website Publications and website
Implications of results Publications and website Publication and website
8. Independent reviews
Current Conformance Level / Target Conformance Level
Extensive
Reviewer(s) name & affiliation: Faculty collaborators and anyone interested
When was review performed? To Be Determined
How was review performed and outcomes of the review? To Be Determined
9. Test competing implementations
Current Conformance Level / Target Conformance Level
Extensive
Yes or No (briefly summarize)
Were competing implementations tested? Yes. Our Lab tests multiple model types routinely.
Did this lead to model refinement or improvement? Yes. We continue to develop simplified models in parallel, to gain insights.
10. Conform to standards
Current Conformance Level / Target Conformance Level
Extensive
Yes or No (briefly summarize)
Are there operating procedures, guidelines, or standards for this type of multiscale modeling? Yes, by NEURON and BMTK software developers. Not in general yet.
How do your modeling efforts conform? Testing by users will determine acceptability
11. (optional) Additional information to support items 1-10

Models of neurons and networks continue to be developed at multiple levels by many Labs, including ours. Standards for assessment of the models typically starts with a match with biological data, i.e., validation. After that key criterion for assessing the utility of the models is whether it can provide testable predictions for the the neuroscientists, and for device-development teams. The focus of our project is to develop sand-box models to enable users to test 'what if' scenarios that they can design to explore testable predictions of interest to them.