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Neurogastroenterology Muscle Architecture & Disease Mechanisms

The scientific underpinnings of the Foundation for Neurogastroenterology Health feature the physical and molecular determinants of muscle structure and function. To better understand and treat neuro-gastroenterological disease, we developed a research platform incorporating advanced imaging, computational mechanics, bioenergetics, and systems biology, notably:
  • Diffusion-based MR methods to image architectural tissue injury through the interrogation of Q-space.
  • Characterization of muscle motion and force based on multiscale computational models derived from myoarchitecture, myofilament interactions, and biological energy.
  • Adaptive and maladaptive remodeling in muscle, including mechanisms of cytokine-driven cellular plasticity, architectural response to injury, and pathological mechanics.
  • Pathological neuroimmune functions associated with gastroparesis.
  • Technology that uses light to generate oxygen from biological fluids through photocatalysis.

Specific elements of the Foundation’s Research Portfolio include:

Architectural “design” of muscular tissue detected with Q-space MRI (QSI)

We have developed diffusional MR methods to map biological architecture and aligned mechanical function. Through QSI, MR signals derived from proton diffusion can be represented as a function of the oriented strength and duration of diffusion encoding magnetic gradients, whose outcome is a geometrically patterned image of tissue myoarchitecture (Figure 1). With this approach we have considered lingual, gastrointestinal, and cardiac muscle as a hierarchical array of myofibers, with the tissue defined simultaneously at the microscopic (single fiber), mesoscopic (multi-fiber arrays) and macroscopic (tissue) scales

[Figure 1. Imaging biological architecture with QSI.

A) Q-space paradigm with 256 gradient directions to demonstrate angular resolution in terms of facet size and orientation. B) Q-space shown as a set of directionally color-coded gradient vectors. C) Probability distribution function (PDF) including the intensities and directions of proton diffusion as a function of B value (diffusion sensitivity). D) PDF shape defined at specified angular separations (90°, 60°, and 45°) in the setting of increasing B values. The PDF is used as a template in muscular tract generation, using a streamlining algorithm E), resulting in angular resolution of crossing tracts in 3D reconstructions (F). G) Architectural image of the bovine tongue representing the multi-scale attributes of the aligned fiber populations revealed by QSI.]

Representative publications

Napadow VJ, Q Chen, VJ Wedeen, RJ Gilbert. Intramural mechanics of the human tongue in association with physiological deformations. J Biomechanics, 32: 1-12, 1999

Napadow VJ, Chen Q, Mai V, So PTC, Gilbert RJ. Quantitative analysis of three- dimensionally resolved fiber architecture in heterogeneous skeletal muscle tissue using NMR and optical imaging methods. Biophysical J, 80: 2968-2975, 2001.

Gilbert RJ, Magnusson LH, Napadow VJ, Benner T, Wang R, Wedeen VJ. Mapping complex myoarchitecture in the bovine tongue with diffusion spectrum magnetic resonance imaging. Biophysical J, 91(3):1014-22, 2006

Felton SM, Gaige TA, Benner T, Wang R, Wedeen VJ, Reese TG, Gilbert RJ Association of mesoscale myofiber organization with local strain rate during swallowing. J Biomechanics, 41(3): 1782–1789, 2008.

Taylor EN, Hoffman MP, Aninwene II GE, Gilbert RJ. Patterns of intersecting fiber arrays revealed through the assessment of whole organ myoarchitecture. Biophysical J, 108(11): 2740-9, 2015

Mechanical nexus linking sarcomere biology, myoarchitecture & force

The distribution and orientation of muscle fibers contribute to the mechanics of deformation and force. As an example, the high level of structural redundancy exhibited by the tongue’s muscular organization suggests that it best be considered as a continuous material, whose material properties and activations define its contractility. We initially developed a solid phase computational model of lingual mechanical function to link its underlying molecular and macroscopic behavior. We subsequently enhanced this model to depict the microscopic material characteristics of lingual muscle via the introduction of Huxley’s model and then evolved a method to associate derived solid phase deformation with bolus flow. Our approach leverages data representing cell activation, tissue deformation and force, and bolus flow to yield a 3D coupled solid-fluid model that predicts normal or abnormal swallowing from force-generating deformation (Figure).

[Figure 2. Coupled solid fluid model of lingual deformation during swallowing that predicts patterns of oropharyngeal bolus flow.

We describe a multiscale formulation of the deforming tongue during the swallow, through (I) the generation of a convolutional neural network (CNN)-enhanced Q-space depiction of lingual myoarchitecture, (II) the determination of multiscale solid mechanics, and (III) the representation of a fluid model showing the relationship between FEM-derived lingual surface deformation and bolus flow (III). The details of the multi-scale solid model are depicted in hierarchical sequence (second row) in terms of: A) QSI tractography discretized into finite elements, B) diagram depicting muscle fibers contained within a characteristic FE, C) elongation (stretch) of an individual muscle fiber, and D) Huxley skeletal muscle model employing intra-sarcomere energetics.]

Representative publications

Napadow VJ, RD Kamm, RJ Gilbert. Biomechanical model of sagittal bending for the human tongue. Journal of Biomechanical Engineering, 124: 547-556, 2002.

Mijailovich SM, Liang A, Wedeen VJ, Gilbert RJ. Simulation of lingual tissue deformation based on the mechanics of mesoscale myofiber tracts obtained by diffusion spectrum MR imaging with tractography. Journal Applied Physiology, 109(5):1500-14, 2010.

Stojanovic B, Svicevic M, Kaplarevic-Malisic A, Gilbert RJ, Mijailovich SM. Multi-scale muscle contraction model linking sarcomere length-dependent cross-bridge kinetics with macroscopic deformation. Journal of Computational Science, 39:101062, 2020

Leichter DM, Stark N, McFarland S, Leary OP, Gilbert RJ,* Nicosia MA.* Development of a coupled computational model relating myoarchitecturally derived lingual deformation with liquid bolus flow during oropharyngeal swallowing. Computers in Biology and Medicine, 145: 105446, 2022. * Shared senior author.

Phosphoregulation of muscle cells & myoarchitecture

Geometric alignment of cardiac myocytes in the ventricular wall constitutes the anatomical template upon which myocyte contractility and electrical conductivity occur. Accordingly, altered geometric patterns across the ventricular wall constitute a measure of heart pump failure in the setting of cardiomyopathy. An important point of convergence for multiple signaling pathways in the cardiac sarcomere is the myosin binding protein C (MYBPC3) phosphoregulatory locus. We developed a geometric model relating cardiac work to ejection fraction from which we deduced that altered phosphorylation of MYBPC3 contributes to the genesis of abnormal ventricular wall geometry revealed by various forms of microscopy and Q space MRI (Figure).

[Figure 3. Mechanisms by which MYBPC3 phospho-regulation affects sarcomere stability and cardiac myoarchitecture.

We postulate that phosphorylation of MYBPC3 results in reduced myosin binding and enhanced thick and thin filament cross-bridge kinetics, thus stabilizing the sarcomere during force (A), with MYBPC3 M-domain labeled in green. In the dephosphorylated state, enhanced myosin binding with reduced cross-bridge kinetics destabilizes the sarcomere (B), with the M-domain labeled as red. For transgenic animals, the phospho-mimetic mutation sarcomere is constitutively stabilized, whereas in the phospho-ablation mutation, the sarcomere is constitutively destabilized.]

Representative publications

Wang TT, Kwon HS, Dai G, Wang R, Mijailovich SM, Moss RL. So PTC, Wedeen VJ, Gilbert RJ. Reduced expression of myosin binding protein C (MyBP-C) is associated with myoarchitectural disarray in the mouse ventricular wall. Annals Biomedical Engineering. 38(9): 2841-50, 2010.

Taylor EN, Hoffman MP, Barefield DY, Aninwene II GE, Abrishamchi AD, Lynch TL, Govindan S, Osinska H, Robbins J, Sadayappan S, Gilbert RJ. Alterations in multi-scale cardiac architecture in association with phosphorylation of myosin binding protein-C. JAHA, 5(3): e002836, 2016.

Barefield DY, Lynch IV TL, Kuster DWD, Haar L, Wang Y, McNamara J, Taylor EN, Pradeep L, Dobev D, Ai X, Janssen PML, Kass D, J WK, Gilbert RJ, Sadayappan S. Ablation of the calpain-targeted site of cardiac myosin binding protein-C is cardioprotective during ischemia.J Mol Cell Cardiol. 129:236-246, 2019.

Arif M, Rafsanjani P, Song T, Desai D, Singh R, Kondori SB, Gilbert RJ, Dhandapany PS, Becker RC, Kranias EG, Sadayappan S. Genetic, clinical, molecular, and pathogenic aspects of the South Asian-specific polymorphic MYBPC3Δ25bp variant. Biophysical Reviews, 12(4): 1065-1084, 2020.

Lynch TL, Kumar M, McNamara JW, Kuster DWD, Sivaguru M, Pervis MJ, Kyoung HL, Kuffel G, Zillox MJ, Lin BL, Weikang M, Gibson A, Blaxall BC, Lorenz JN, Leichter DM, Leary OP, deTombe PP, Gilbert RJ, Craig R, Irving R, Warshaw DM, Sadayappan S. Amino terminus of cardiac myosin binding protein-C regulates cardiac contractility. J Mol Cell Cardiology, 26;156:33-44, 2021.

Fibroblast transdifferentiation & inflammofibrotic injury

Muscle injury is characterized by complex interactions involving fibroblasts and immune cells that collectively form the backbone of regenerative repair in the heart. We have identified a subpopulation of cells expressing surface markers of quiescent cardiac fibroblasts, activated cardiac fibroblasts, and lymphoid T-cells (CD4). We confirmed the presence of spindle-shaped cells dually expressing markers for fibroblasts and T-cells in fibrotic areas of the right ventricle tissue of humans diagnosed with pulmonary hypertension and in rat model pulmonary hypertension. We showed that these resident cardiac fibroblast cells are structurally and functionally similar to lymphoid cells and that they produce a prototypical fibroblast-immune secretome (genome, proteome, metabolome) related to matrix deposition and inflammation when exposed to the pro-inflammatory cytokine IL-1β. Characterization of the IL-1β induced CD4+ population using RNA sequencing suggested a unique genetic identify linked to patterned dedifferentiation and redifferentiation. These findings postulate a role for fibroblasts in the enaction of a “first response” to injury through immune biology (Figure).

[Figure 4. Proposed role of fibroblast transdifferentiation in the pathogenesis of muscle injury.

Based on our experimentation, we propose that resident cardiac fibroblasts undergo staged polarization and phenotypic switching in response to proinflammatory signals, such as IL-1β, to facilitate repair and cell survival. This results in transdifferentiation to a secretory cell with a lymphoid cell-like phenotype that participates in the amplification and regulation of the inflammatory response through secretion of immunomodulatory proteins, metabolites, cytokines, and chemokines. Enhancing IL-1β may promote the participation of resident cardiac fibroblasts in the processes of inflammation and repair.]

Representative publications

Siamwala JH. Zhao A, Barthel H, Gilbert RJ, Rounds S. Innate immune mechanisms in cardiac fibrosis and pulmonary arterial hypertension. Physiological Reports, 8(15): e14532, 2020.

Siamwala JH, Pagano F, Dubliecka-Szczerba PM, Ivey MJ, Guirao-Abad JP, Zhao A, Chen S, Granston H, Jeong JY, Rounds S, Kanisicak O, Sadayappan S, Gilbert RJ. IL-1β-mediated adaptive re-programming of endogenous human cardiac fibroblasts to cells with immune features during fibrotic remodeling. Communications Biology (Nature Portfolio), Nov 25, 6(1): 1200, 2023.

Immunopathogenesis of gastroparesis

We have proposed a model of gastroparesis that employs concepts of neuroimmune plasticity to account for the disease’s extraordinary clinical heterogeneity. We consider that the focus of injury in the gastric wall is the neuroimmune interface, a set of cells that constitute a programmable multicellular network affecting rhythmicity. Extending previous work positing the role of neuroimmune signaling under the regulation of cytokines and lipid mediators, bi-directional control of neuro-immune interfaces, and adaptive immunity reflecting “learned” behavior, we propose that gastroparesis be considered as a neuroimmune pathology (Figure). We postulate that the gastroparetic stomach characteristically responds to injury with the release of cytokines or other mediators from inflammatory cells, resulting in the interruption or modification of intrinsic bio-oscillatory behavior due to interactions involving ICC, myenteric nerves and smooth muscle cells. 

[Figure 5. Model depicting the immunopathology underlying gastroparesis.

We propose a multilevel model that underlies the high degree of biological heterogeneity embodied in the pathogenesis of gastroparetic syndromes. This model embodies biological interactions principally at the neuroimmune interface in the gastric wall and extragastric phenomenon that responds to and modulates this initial interaction. By this model, a gastric wall response to infectious, mechanical, metabolic, or ischemic perturbations triggers inflammatory injury medicated by various spatially arrayed endogenous/exogenous immune cells. This inflammasomic response perturbs oscillatory activation involving the ICC, myenteric nerves, and smooth muscle cells such that local dysrhythmia ensues, leading to pathological contractility.]

Representative publications

Gilbert RJ, Siamwala JH, Kumar V, Thompson CC, Shikora SA. Reconsideration of the gastroparetic syndrome. Current Gastroenterology Reports (Nature Portfolio), 25(4):75-90, 2023.

Sakthivel K, Gilbert RJ. Food as medicine: Establishing a scalable foundation using data-guided and supermarket-based dietary interventions and modern online shopping tools. Thrombosis Thrombolysis, 56(4):514-517, 2023.

Sakthivel K, Van Niel A, Siamwala JH, Thompson CC, Shikora SA, Gilbert RJ. Bidirectional relationship between gastroparesis and malnutrition. Digestive Diseases and Sciences, 70(9):2951-2955, 2025.

Photocatalytic generation of oxygen in biological fluids

Life on Earth is defined by seminal relationships involving oxygen, water, and energy. To support living systems, Nature has evolved mechanisms to generate oxygen from the most basic physical components, namely water and sunlight. Recalling Nature’s solution to life support, photons of solar light are characteristically absorbed by endogenous chromophores during photosynthesis, followed by the displacement of electrons across energy bands, resulting in the generation of positively charged electron “holes” and the separation of electrical charge. The presence of strong surface charge separation promotes the “splitting” of water into oxygen and hydrogen. We have elaborated a technology that emulates the capacity of plants to extract oxygen from water in the unique setting of whole blood (and biological tissue), thereby allowing us to carry out, for the first time, oxygenation without the need for oxygen delivery via the lungs or ventilators. Our core technology utilizes a semiconducting metal oxide material (TiO2) as both the photo-absorption element and the mechanism mediating oxygen generation (Figure). The concept of photolytic life support was described in an initial patent (U.S. Patent 7485261) and then expanded upon by our subsequent research (NIH RO1 HL 086652) establishing a microfluidic-scale photocatalytic respiratory device (U.S Patent submitted).

[Figure 6. Photonic interactions with semi-conducting materials during photocatalysis.

Photocatalytic reactions involve the interface of photons with a transition metal oxide semiconducting substance, resulting in the displacement of electrons from the valence to the conduction band, thus creating electron vacancies. Such vacancies then diffuse to the materials surface, where they promote water splitting to oxygen and hydrogen.]

Representative publications

Vollmer A, RJ Gilbert, T Thorsen. Development of an integrated microfluidic platform for oxygen sensing and delivery. Lab Chip, 5(10):1059-66, 2005

Martin PM, Gilbert RJ,, Burckle EC, Busch J, Dasse KA, Monzyk BF. Photo-activated metal oxide thin films regulate oxygen homeostasis. Journal of Materials Science and Engineering B, Materials Science & Engineering, B: Solid-State Materials for Advanced Technology, 119(3), 246-251, 2005.

Gilbert RJ, Carleton, LM, Dasse KA, Martin PM, Monzyk BF. Photocatalytic generation of dissolved oxygen and oxyhemoglobin in whole blood based on the interaction of UV light with a semiconducting titanium dioxide thin film. Journal of Applied Physics, 102 (7): 073512. 2007

Rasponi M, Ullah T, Gilbert RJ, Thorsen T. Realization and efficiency of a micro-photocatalytic cell prototype
for real-time blood oxygenation. Med Eng Physics, 33(7):887-92, 2011.

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