The dystrophin protein protects cardiac and skeletal muscle from damage during normal contraction and relaxation by acting as a shock absorber in the cell. Mutations in the dystrophin gene lead to Duchenne muscular dystrophy (DMD), an X-linked recessive disease. Boys suffering from the disease become ventilator dependent at a young age and usually succumb to cardiac failure in their thirties. Other symptoms of DMD include muscle wasting, cardiomyopathy and respiratory failure. Currently there is no cure for DMD and while gene therapy has shown great promise, it still needs to be complemented with additional therapeutic interventions in order to fully address the symptoms of DMD. Previous work by our lab identified several drugs that blocked a certain type of calcium channel in cardiac muscle and protected the cells from damage following injury by correcting calcium movement into and out of the cell during muscle contraction. In this study, the leading drugs will be tested further using a cross-platform approach. The drugs will initially be tested in cardiac and skeletal muscle differentiated from healthy and DMD patient-derived induced pluripotent stem cells (iPSCs). The top three drugs that restore normal contraction and relaxation kinetics in vitro will then be tested in the DMDmdx rat. This novel, small animal model has a similar progression of DMD symptoms to human patients. The rats will be fed the drugs in their chow. Skeletal and cardiac muscle performance will be evaluated to determine whether correcting muscle contraction kinetics ameliorates the symptoms of DMD. Furthermore, we will show whether the same drug is equally effective in treating both cardiac and skeletal muscle. The cross-platform approach may help to better predict drug efficacy, leading to a reduced rate of failure in clinical trials. Moreover, this approach may serve as a benchmark for drug discovery in other neuromuscular diseases.

In 2018, tuberculosis (TB) was the leading cause of death by a single infectious disease, causing 10 million new cases and 1.5 million deaths. Upon Mycobacterium tuberculosis (Mtb) infection most people develop non-transmissible latent TB, and some develop active TB disease. Healthy hosts have a 5-15% lifetime risk of progressing from latent to active TB, and prior studies have demonstrated that a type I interferon-stimulated gene (ISG) signature can predict progression to active disease. Type I interferon (IFN) and ISG expression is induced by DNA-sensing pathways and has anti-viral functions. However, the innate immune mechanisms and genetics controlling type I IFN responses following Mtb infection are not well understood. We hypothesize that genetically regulated higher type 1 IFN responses are associated with lower anti-microbial responses and higher Mtb replication in macrophages, as well as increased risk of TB disease. To test this hypothesis, blood was collected from 40 healthy donors. Donors were genotyped using Illumina MEGA^EX SNP Array. Monocytes were isolated, differentiated into monocyte-derived macrophages (MDMs), and stimulated with 3 ligands (supercoiled plasmid DNA, cyclic guanosine monophosphate–adenosine monophosphate, and sheared calf thymus DNA) to activate DNA-sensing pathways and induce a type I IFN response. RNA was isolated at 4 and 24 hours. Interferon-beta (IFN-β) and interleukin-6 (IL-6) gene expression were quantified using Real-Time PCR. Donors had highly variable IFN-β induction upon ligand stimulation. Donors’ genotypes will be linked to these in vitro phenotypes to identify expression quantitative trait loci (eQTLs) that regulate IFN-β expression. We will assess if these functional polymorphisms in genes of interest are associated with TB disease using patient samples from a Brazilian cohort. The results of this investigation will identify novel pathways that control TB progression that can inform vaccine development and host-directed therapeutic approaches.

There is a long-standing concern that in American society, historical roots, structural racism, and systems of power have perpetuated the spectrum of negative health outcomes in communities of color. As the status quo is maintained, policy and public opinion reflect the continual oppression of minority families. Through my research, I created a visual and multimedia project that will identify the relationship between public policy and the social determinants of health, and how these factors have affected different communities of color within Washington state and the national level. I conducted extensive library research, analyzed and interpreted data, and utilized GIS technologies to visualize the placement of different communities. This work includes identifying historical background information, past U.S. policies, and relevant literature. In this visual and multimedia project, I displayed four puzzle pieces representing different communities (Asian, Native American, Hispanic, and African Americans) on a map, and examined public policies implemented by European colonizers that racialized minorities in unique ways. This chronological project displayed contemporary policies in housing, economic, employment, education, and criminal justice. Overall, I looked at each group's distinct experience of racial health disparities and will use this platform for dialogue to emerge for students and community members on these topics to prioritize the needs, barriers and solutions to confront racism.

Millions of people have vision diseases that are not yet treatable, leading to blindness. Mouse models exist for some inherited retinal diseases, and thus have helped develop vision loss therapies. However, other common retinal diseases like glaucoma lack accurate mouse models. Human pluripotent stem cells (hPSCs) are a promising technology that provide a new way to model human retinal diseases. hPSCs can be induced to become layered, 3D mini-retinas called retinal organoids. Retinal organoids mirror early neurogenesis of the human retina, and thus can be used for modeling developmental disorders. However, we and other research groups have shown that as retinal organoids mature, they lose many features of the normal human retina. In particular, the neurons that are damaged during glaucoma, called retinal ganglion cells (RGCs), are not well preserved in organoids. As the organoid matures, the RGC layer becomes disorganized and RGCs migrate through the retina. RGCs are the projection neurons of the human retina, so their axons extend through the optic nerve and carry visual information to the brain. Unlike in human development, retinal organoids are grown in isolation from their brain targets. We wondered whether we could preserve RGC organization by providing organoid RGCs with synaptic targets. We investigated this hypothesis by combining the retinal organoids with their natural targets in the brain, the lateral geniculate nucleus and the superior colliculus. It is not yet known how to make these brain regions from hPSCs, so we used newborn mouse brain and combined the retinal organoids with these brain regions into structures called “assembloids.” We are now testing whether these assembloids preserve the RGC survival and laminar organization that retinal organoids lack. Promoting RGC survival and organization will allow organoids to become better in vitro models for glaucoma and improve the outcome for patients with vision loss.

Since Computed Tomography (CT) scans expose the patients to high x-ray radiation dose which may potentially induce lifetime risk of cancers, researchers have been finding ways to reduce the radiation dose while maintaining the high quality of reconstructed images. One approach to lower the total X-ray radiation dose is to reduce the number of projections acquired, which generated sparse-view CT image. However, when the number of view angles is too less to satisfy the Shannon/Nyquist sampling theorem, serious streaking artifacts will appear on the reconstructed images. In this work, we present two iterative reconstruction algorithms, which implement convolutional neural networks (CNN) in each iterative step, to help eliminate these defects. The first algorithm is LEARN, which uses a CNN in place of a regularization function while solving a least squares problem. The second algorithm is based on SART and the superiorization methodology (an iterative method for constrained optimization), where the CNN is used to perturb the solution between SART iterations. We use Tensorflow and the Pyro-NN library in Python to train on data obtained from The Cancer Imaging Archive’s QIN LUNG CT dataset, and compare the performance of these two frameworks from the perspectives of PSNR value (often used to exam the quality of an image), training loss, penalty term, and learning rate. Besides testing on different sparse-view imaging datasets, we also demonstrate the performance of the proposed networks in limited angle CT image, where some view angles are missing due to geometric constraints.

Retinal diseases tend to affect specific neuron subtypes, ranging from age-related macular degeneration, which is caused by the deterioration of photoreceptors near the central portion of the retina (macula), to glaucoma, in which abnormally high intraocular pressure leads to ganglion cell death. Unfortunately, adult mammals are not able to regenerate retinal neurons. However, zebrafish and other amphibians can completely regenerate their retinal neurons in many different models of damage, and restore retinal structure and visual function. The source of regeneration stems from the resident Müller glia cells, which normally provide neuronal support and span all three retinal layers. A critical gene for the initiation of transforming Müller glia into neurons was found to be Ascl1. This led our lab to hypothesize that the introduction and upregulation of Ascl1 in mammalian Müller glia might stimulate them to become retinal neurons after damage, as occurs in these other regenerating species. Indeed, after introducing Ascl1 into the Müller glia of mice, we found newly regenerated retinal interneurons (bipolar cells) that successfully integrated into the retinal circuitry and functionally responded to light stimulus. In addition to Ascl1, we have identified two other transcription factors, that when introduced in combination with Ascl1, stimulate the generation of two different retinal neurons (ganglion cells and amacrine cells). We are currently developing a model of glaucoma, damaging the ganglion cells with a neurotoxin, and then testing the visual acuity using Optomotry to determine whether regenerated ganglion cells will mediate a functional improvement. Ectopic expression of a proneural transcription factor to stimulate retinal regeneration provides a potential therapeutic intervention for treating blinding diseases, that even now, have few modest treatment options.

Jim Crow era legalized racism denied Black women the freedom to exercise control over their childbearing and childrearing; specifically, by restricting their access to necessary medical care and sufficient resources to care for their families, and by constraining their autonomy and agency. As a consequence, Black women experienced uniquely poor reproductive health and family outcomes compared to all other racial and ethnic groups (Eichelberger et al. 2016); these racial disparities persist today. This study applies a reproductive justice framework to understanding Black women’s lived experiences of systematic raced and gendered oppression, as well as their forms of resistance when caring for themselves and their children. Reproductive justice is the personal right to control one’s body, have children under the conditions that we choose, and parent those children in stable communities (Sister Song 1997). Thus, we ask how did gendered racism impact Black women’s experiences of reproductive justice and what strategies of resistance did they devise in response? We used Dedoose, a cloud-based mixed methods software, to conduct a content analysis of oral histories from two oral history repositories. These primary sources were excerpted and coded for common themes including racism’s influence on childbearing and childrearing, socioeconomic experiences, access to medical care, and protective factors. We have three preliminary findings that contribute to existing literature: 1) when women required more medical care than midwives could provide, they experienced numerous barriers to accessing such care, 2) Black women experienced multiple levels of social control that undermined their childrearing, and 3) women devised strategies of resistance to care for their bodies and their children, including collective childrearing, resource sharing, and instilling a sense of self-worth in their children.

Marine heatwaves are the phenomena of abnormally warm ocean surface temperatures that last for an extended period of time. The most severe marine heatwave of recent times occurred from 2013 to 2016 in the Northeastern Pacific. This event, nicknamed ‘The Blob’, was scientifically fascinating because the ocean-atmosphere system maintained itself for so long in an anomalous state. In mid-2019, a marine heatwave with a likeness to ‘The Blob’ began forming. This research project focuses on analyzing the anomalous patterns in sea surface temperature, clouds, radiative fluxes, and turbulent fluxes that arise during the formation and duration of this event. We set out to understand if the more recent 2019 marine heatwave evolves in a similar way to that of ‘The Blob,’ and how it differs. This project uses NOAA Climate Forecast System Reanalysis (CFSR) data, which assimilates measurements using complex models to create the best estimates of atmospheric and oceanic variables with complete global spatial coverage. With this project, we aim to understand the atmospheric response to marine heatwaves using geospatial plots of mean temperature, fluxes, and cloud cover. We expect to see differences in the atmosphere response with regards to the net flux that caused the quick dissipation of the recent marine heatwave.