Ongoing Research Projects
Mouse neural-glial metabolic modeling for exploring the FABP7 circadian-sleep-metabolism node in neurological health
According to the astrocyte-neuron lactate shuttle hypothesis (ANLSH), strong metabolic coupling occurs between astrocytes and neurons, with the astrocyte serving “protective” and “supportive” roles for the neurons. Increased neural activity during “wake” periods, associated with glutamine “wake” signaling, leads to increased accumulation of fatty acids leading to increased production of reactive oxygen species (ROS) which induces lipid peroxidation, leading to disruption in neuronal membrane integrity. Astrocytes protect neurons from fatty acid- and excito- toxicity by the uptake of fatty acids and glutamate (produced during “wake” periods), particularly at the tripartite synapse, and shuttle lactate to neurons supporting wake-associated increased neural activity. It is hypothesized that sleep pressure builds with increased energy generation in neuronal mitochondria, in part through the export of ATP from astrocytes and somnogenic effect of adenosine, and the role of sleep is to synthesize lipids, repair and maintain cell membranes, and scavenge ROS. High lipid accumulation in astrocytes and dysregulation or disruption of lipid metabolism is associated with seizures, excitotoxicity, and epilepsy disease progression. A key component in fatty acid trafficking at the tripartite synapse is Fatty acid binding protein 7 (FABP7), an astrocyte-enriched circadian clock-controlled protein that regulates the subcellular trafficking of fatty acids. Required for normal sleep, Fabp7 is also known to affect gene transcription, metabolism, neural-glial interactions, and lipid storage. Increased Fabp7 expression is associated with traumatic brain injury (TBI), and the dysregulation of Fabp7 expression has been implicated in a wide range of neurological diseases, including Alzheimer’s disease (AD), Down syndrome, Parkinson’s disease (PD), depression, and glioblastoma tumorigenesis. We propose that FABP7 is a molecular “node” that integrates circadian rhythms, sleep, metabolism to facilitate neurological health. However, the potential role of FABP7 as a molecular node is only now being appreciated and investigated. Initial in vivo studies suggests that there is an as-yet uninvestigated link between FABP7 and diurnal metabolism that is crucial for gaining a systems-level understanding of neural-glial mediated neural health. Given their strong metabolic links and regulation by proteins, reconstructions of global neural-glial networks of metabolic interactions incorporating all chemical reactions constrained by enzyme abundance (called Resource Allocation Models, or RAMs) are potentially invaluable tools for improving systems-level understanding.
Experimental Collaborator:Jason Gerstner
In silico engineering of heterocyst-forming cyanobacteria for inducible carbon dioxide and light to bioproduct platforms
Motivation: Human-caused climate change is threatening the global ecosystem with myriad political, human, economic, and ecological effects stemming from these changes. A popular idea to mitigate further climate change is the development of a circular carbon economy, for which carbon capture and upcycle technology will play a key role. The development of carbon-negative platforms to produce biofuels or chemical feedstocks which replace petrochemicals will be one key carbon capture technology. Cyanobacteria are emerging chassis for carbon-neutral bioproduction due to key advantages such as higher photosynthetic efficiency, ease of genetic manipulation, and being prokaryotic. Diazotrophic (nitrogen-fixing) cyanobacteria can be a CO2 to biochemical chassis which requires few inputs. As nitrogen fixation is strongly inhibited by oxygen, in some species specialized, terminally differentiated, heterocyst cells to create anoxic environments. While often slow-growing, it offers the opportunity of an inducible system, as nitrogen starvation induces cell differentiation, and large changes in transcriptional regulation which could be harnessed to bioproduction without forsaking photosynthesis. This research aim would be interested in designing an inducible biochemical production platform using heterocyst forming cyanobacteria, where cells are grown to a desired density, followed by bioproduction triggered by nitrogen starvation and facilitated by cellular differentiation. This would minimize competition between growth and bioproduction.
Objectives: This project will apply model reconstruction techniques, computational modeling tools, and available transcriptomic and proteomic datasets to i) reconstruct a GSM of model heterocyst forming cyanobacteria Anabaena sp. PCC 7120; ii) Use those reconstructions as bases to develop normal and differentiated Anabaena cell models; iii) incorporate these two models into a “beads on a string” model of differentiated, nitrogen-starved Anabaena filaments which models diffusion of carbon and nitrogen; and iv) use differentiated models to design an inducible system for biochemical production.
