Madeline McLaughlin: STIM1 Interacts with G Protein-Coupled Estrogen Receptor Signaling to Maintain β Cell Identity in Female Mice

Abstract: Calcium (Ca²⁺) plays a vital role in normal pancreatic β cell function, and the β cell endoplasmic reticulum (ER) serves as the dominant intracellular store of Ca²⁺. ER Ca²⁺ depletion triggers a rescue mechanism known as store-operated Ca²⁺ entry (SOCE), which replenishes ER Ca²⁺ stores through the ER-localized Ca²⁺ sensor stromal interaction molecule 1 (STIM1). We have demonstrated pathogenic reductions in β cell SOCE and loss of STIM1 expression in rodent and human models of type 2 diabetes (T2D) and shown that β cell-specific loss of STIM1 (STIM1Δβ) leads to obesity-induced glucose intolerance, decreased β cell and increased  cell mass in female but not male STIM1Δβ mice. RNA sequencing of islets isolated from female STIM1Δβ mice revealed reductions in G-protein coupled estrogen receptor (GPER) expression and a transcriptional signature indicative of reduced estradiol mediated signaling. To test whether GPER is required for the maintenance of β cell identity, INS-1 cells were transfected with siRNA targeted to Gper1 or treated with the GPER1 antagonist, G-15. RT-qPCR showed that markers of β cell identity were significantly reduced and Gcg expression was significantly increased in Gper1 knockdown and G-15-treated cells. Lastly, to determine the relationship between estradiol signaling and β cell identity, we performed ovariectomy surgeries in female mice and showed that loss of estradiol signaling leads to obesity-induced glucose intolerance. Further experiments are warranted to determine the differentiation status of the β cells in the ovariectomized mice and the mechanisms behind this connection. Together, these data identify a novel connection between β cell SOCE, GPER signaling, and β cell differentiation status.

Evaluation link for Madeline McLaughlin: https://purdue.ca1.qualtrics.com/jfe/form/SV_b7b3MGYdztRV7gy

Shatha Mufti: Assessment of Seizure-Like Activity in Neuronal Networks Post-Traumatic Brain Injury Utilizing Novel TBI-On-A-Chip Model

Abstract: Traumatic brain injury (TBI) is a leading cause of death and long-term disability worldwide. Further, seizure development is one of the most serious sequalae post-TBI. Unfortunately, the underlying mechanisms connecting TBI and seizures are not well understood. Identifying cell-scale pathophysiological changes in the brain post-injury will be paramount for identifying therapeutic targets. Cell membrane damage, which results from the uncontrollable cell stretching upon injury, is considered one of the main causes of cellular ionic imbalances and biochemical changes that can lead to the deterioration of TBI cases. Membrane permeability changes caused by membrane breaches may increase the susceptibility of cells to seizure-like activity (SLA) with increased cell depolarization. Furthermore, as neuronal networks try to reorganize around the injury site, hyperexcitability of networks may result, which leads to increased seizure susceptibility. Polyethylene glycol (PEG), a hydrophilic polymer and known fusogen, has shown potential in sealing damaged cell membranes and restoring functional recovery post-TBI in preclinical studies. Therefore, we hypothesize that targeting cell membrane damage therapeutically with PEG would mitigate the reduction in seizure initiation threshold post-TBI. Investigation of PEG treatment effects would be carried out in our unique TBI-on-a-chip system, which simulates the pathophysiology of concussive TBI by applying clinically relevant, rapid acceleration injuries to murine cortical networks on custom microelectrode arrays, while providing real-time, cell-scale monitoring of electrophysiological and morphological changes. Utilizing extracellular recordings of network spike activity, we reveal the spontaneous appearance of SLA in networks exposed to 10 rapidly (4-6 sec) administered 30 g impacts. Furthermore, we attempt to better characterize SLA and burst features to gain critical information about post-injury electrophysiological changes. In summary, our TBI-on-a-chip model could provide vital insights into functional and morphological changes post-TBI, while enabling the investigation of underlying SLA mechanisms, which could lead to the identification of potential therapeutic targets.

Evaluation link for Shatha Mufti: https://purdue.ca1.qualtrics.com/jfe/form/SV_bqtEefXLhwxHdDE

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Meeting ID: 982 3165 9969    Passcode: biomedical