Research Agenda
The Foundation for Neurogastroenterology Health extends the decades-long work of the Gilbert Laboratory
The Foundation is applying pioneering molecular and biophysical concepts to understand the biological underpinnings of muscle and nerve injury and repair. The Research Agenda for the Foundation considers the following three pillars:
Research Pillar 1: Decoding Immune Mechanisms Of Muscle Injury
How We Will Achieve This Goal:
Identification of the fibroimmune mechanisms that cause GI muscle weakness in multiple disease states and the development of novel physico-biological modes of therapy.
Specific research includes:
Determination Of Muscle Structure & Function Through Q-space MRI & Multiscale Computational Models
To consider the myoarchitecture and mechanical function of structurally complex muscles, such as the tongue, heart, and GI tract, we developed and validated an MRI method, termed Q-space MRI (QSI), that employs directional differences of proton diffusivity to map complex anatomical organization and integrate this information into computational models of force and flow.
Inflammofibrotic Mechanisms Of Muscle Injury & Repair
Excessive inflammofibrosis in response to tissue stressors promotes a near universal downward spiral of clinical outcomes. We recently identified a population of fibroblasts that display features of both mesenchymal and lymphoid cells, and showed through lineage tracing that the proinflammatory cytokine, IL-1β, induces fibroblasts to first acquire state of stemness and then re-differentiate into cells with immune attributes. We hypothesize that stress induced modulation of endogenous fibroblasts causes them to de-differentiate and then re-differentiate to either immune cells (reparative phenotype) or myofibroblasts (fibrotic phenotype) depending on the features of the arrayed inflammasomal perturbants in the particular tissue environment.
Architectural Aging In Alzheimer’s Disease
We hypothesize that DNA modulation and inflammofibrotic injury in muscle underlie the genesis of pathological architectural phenotypes linked to Alzheimer’s Disease. We postulate that architectural aging of muscle is based on epigenomic conditions that lead to the activation of inflammatory pathways, induction of a fibrotic (non-reparative) phenotype, and mechanopathology. We will test the hypothesis that age-based activation of retrotransposons results in accelerated inflammofibrosis and architectural disarray in Alzheimer’s Disease, and that such effects are modified by the silencing of retrotransposons, reduced interferon activity, or adaptation of fibroblast plasticity.
Research Pillar 2: Developing Targeted Gastroparesis Therapy
How We Will Achieve This Goal:
Purposefully remodeling the critical neuroimmune interface using advanced gene editing, local oxygen delivery, and polymer-encapsulated cytokines that may be delivered directly to the nerves and muscles of the stomach. Specific research includes:
Immunopathogenesis Of Gastroparesis
We hypothesize that biological modulation of endogenous
fibroblasts adjacent to the ICC promote adverse remodeling during gastroparesis. The focus of our research is to define the critical pathways for regulating neuroimmune interactions and to then develop pharmaco-therapeutic paradigms to remodel these pathways. We propose to use endoscopic full-thickness tissue sampling in order to constitute myenteric plexus organoids that will serve as a testbed for assessing the effect of cytokines and cytokine combinations in individual patients, with emphasis on patients with Ehlers Danlos Syndrome, and thus develop unique therapeutic solutions.
Develop Immunomodulatory Treatments Of Inflammatory Gastric Pathology Based On The Submucosal Delivery Of Nanoencapsulated Cytokines
Research Pillar III: Understanding The Relationship Between Nutrition, Metabolism & Inflammatory Injury
How We Will Achieve This Goal:
Identify pathways that associate nutrition, inflammation, and metabolism in the wall of the GI tract, and thereby demonstrate the role of nutrient replacement as a primary therapy for neurogastroenterological diseases. Specific research includes:
Establishment Of A Research Program For The Study Of Advanced Metabolic & Nutritional Diseases
We will study the pathways linking nutrient supply, metabolism, hormonal regulation, and inflammofibrosis in the setting of foregut motility abnormalities, such as gastroparesis (Figure). The relationship between malnutrition and GI disease is inherently bidirectional since GI pathology may affect nutrient accessibility, which, in turn, affects the expression of inflammomodulatory factors that modulate the underlying GI pathology. We specifically postulate that nutrient deprivation induces inflammation via mTOR-directed pathways that, in turn, modulate the structural and biological organization of the myenteric plexus and thereby affect gastric nerve rhythmicity and the symptoms of gastroparesis.
Bidirectional Relationship Involving Malnutrition & The Gastroparetic Syndrome
We propose a two-way relationship of cause and effect involving the gastroparetic stomach and nutrients. By this model, impaired gastric motility resulting from gastroparesis results a reduction of nutrient delivery to the enteral absorptive surface and yields a reduction or elimination of nutrients to the gastric wall. Nutrient deprivation in turn down-regulates gastric motility by modulation of mTORC1 or mTORC2 pathways and lysosomal proteins responding to nutrients, either directly in target cells or indirectly via the promotion of macrophage polarization and inflammasomal activation. We suggest that these events promote reprogramming of the biological oscillators involved in gastric motor control and the accentuation of gastric dysmotility.
