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May 15, 2020 Mary Gates Hall May 15, 2020 Mary Gates Hall equally effective in treating both cardiac and skeletal muscle. SESSION O-1F The cross-platform approach may help to better predict drug efficacy, leading to a reduced rate of failure in clinical trials. HEALTH SENSING AND MODELING Moreover, this approach may serve as a benchmark for drug discovery in other neuromuscular diseases. Session Moderator: Alex Mariakakis, Computer Science and Engineering 11:00 AM to 12:30 PM SESSION O-2E * Note: Titles in order of presentation. A Cross Platform Study to Treat Duchenne Muscular PROTEIN BIOCHEMISTRY Dystrophy Session Moderator: Adam Steinbrenner, Biology Aniruddh Saxena, Senior, Bioengineering 1:00 PM to 2:30 PM Mary Gates Scholar, UW Honors Program * Note: Titles in order of presentation. Mentor: David Mack, Rehabilitation Medicine & Bioengineering, Institute for Stem Cell and Regenerative Evolution of a Self-Assembling Synthetic Nucleocapsid Medicine with Enhanced mRNA Packaging Mentor: Shawn Luttrell, Rehabilitation Medicine June Kim, Senior, Bioengineering Levinson Emerging Scholar, Mary Gates Scholar The dystrophin protein protects cardiac and skeletal muscle Mentor: David Baker, Biochemistry from damage during normal contraction and relaxation by Mentor: Issa Yousif, Bioengineering acting as a shock absorber in the cell. Mutations in the dys- trophin gene lead to Duchenne muscular dystrophy (DMD), RNA-based therapeutics have attracted significant interest as an X-linked recessive disease. Boys suffering from the dis- a promising alternative to traditional cancer therapy methods. ease become ventilator dependent at a young age and usu- Coupled with other technologies such as the application of ally succumb to cardiac failure in their thirties. Other symp- nanocarriers, RNA-based treatments have shown the poten- toms of DMD include muscle wasting, cardiomyopathy and tial to regulate gene expression in tumor cells with high ef- respiratory failure. Currently there is no cure for DMD and ficacy and reduced safety risks. Despite these advantages, while gene therapy has shown great promise, it still needs to delivering sufficient amounts of therapeutic cargo while es- be complemented with additional therapeutic interventions in caping from the proteolytic environment of the endosome has order to fully address the symptoms of DMD. Previous work remained a long-standing challenge. This project focuses on by our lab identified several drugs that blocked a certain type addressing this issue by evolving the I53-50-v4 (V4), a self- of calcium channel in cardiac muscle and protected the cells assembling synthetic protein nanoparticle engineered to en- from damage following injury by correcting calcium move- capsulate its own mRNA, to increase RNA packaging and ment into and out of the cell during muscle contraction. In prevent degradation upon endocytosis. With previous data this study, the leading drugs will be tested further using a suggesting a decrease in mRNA encapsulation with an in- cross-platform approach. The drugs will initially be tested in crease in mRNA length, additional designs were generated to cardiac and skeletal muscle differentiated from healthy and further validate this finding. Furthermore, different variations DMD patient-derived induced pluripotent stem cells (iPSCs). of de novo pH-responsive trimers for endosomal escape were The top three drugs that restore normal contraction and re- fused to the exterior of the V4 and tested for RNA packaging. laxation kinetics in vitro will then be tested in the DMDmdx Using computational tools, algorithms were also developed rat. This novel, small animal model has a similar progres- to model the porosity of the nanoparticle and to label residues sion of DMD symptoms to human patients. The rats will for cationic mutations. Protein nanoparticles were expressed be fed the drugs in their chow. Skeletal and cardiac muscle and purified via Immobilized Metal Affinity Chromatography performance will be evaluated to determine whether correct- (IMAC) and SEC (Size Exclusion Chromatography). Con- ing muscle contraction kinetics ameliorates the symptoms of structs were then analyzed in their mRNA encapsulation lev- DMD. Furthermore, we will show whether the same drug is els through RT-qPCR. Success of this project would demon- Undergraduate Research Program 1 www.uw.edu/undergradresearch strate an increase in encapsulation levels with a decrease in lapse, therefore the results from this experiment can provide mRNA length. As the phenotype of each nanoparticle design prospective molecular pathways to target for future studies in is spatially linked to its genotype, the top performing designs treating opioid withdrawal symptoms. Reducing the severity can also be selected and further evolved using both experi- of withdrawal would thus allow ease in discontinuing opioid mental and computational approaches. This will allow the use and diminish relapse. development of a novel assay for screening desired proteins and narrow the gap towards achieving an efficacious RNA- delivery system. SESSION T-2F SESSION T-2C MEDICINE,PATHOLOGY, PHARMACOLOGY, AND BIOETHICS PSYCHOLOGY,SOCIAL WORK, 10:05 AM to 10:50 AM * Note: Titles in order of presentation. PSYCHIATRY &BEHAVIORAL SCIENCES Creating a Pre-Transplant Machine Learning Model for Predicting Infection in Patients with Multiple Myeloma 10:05 AM to 10:50 AM Adam Samir Alayli, Senior, Materials Science & Engineering * Note: Titles in order of presentation. Mentor: David Coffey, Department of Medicine Behavioral Effects of Inhibiting P2Y12 Receptors in Infection is the most common cause of mortality among pa- Microglia during Fentanyl Withdrawal tients with multiple myeloma undergoing autologous stem- Emily K Vo, Senior, Biochemistry, Chemistry cell transplant. Understanding the risk factors that lead to UW Honors Program higher probability of infection is instrumental in their pre- Mentor: John Neumaier, Psychiatry vention. Although some risk factors are known, there are no Mentor: Kevin Coffey, Psychiatry and Behavioral Science robust predictive models for infection among myeloma pa- Mentor: David Bergkamp, Pharmacology tients receiving a hematopoietic stem-cell transplant. In this research study, we compared a variety of machine learning Prescribed opioids are the most common analgesic used for algorithms to reveal clinical features pre-transplant that are alleviating acute and chronic pain. Despite this positive at- most predictive of infection post-transplant. Using features tribute, opioids are also highly abused drugs that can lead to extracted from the electronic health record by means of nat- tolerance and dependence. This abuse has caused a dramatic ural language processing and manual abstraction, we trained increase in opioid overdose-related deaths over the past cou- our model using patients diagnosed with multiple myeloma ple of decades, deeming it a crisis. However, cessation of who received an autologous stem-cell transplant at the Seat- opioid use in tolerant individuals who wish to detoxify can tle Cancer Care Alliance. Along with being robust to missing precipitate severe withdrawal symptoms, often leading to re- data, the model is capable of processing diverse, heteroge- lapse in order to avoid experiencing these negative symptoms. neous data and identifying a class of predictive factors that In recent studies, modulation of neuropathic and neuroinflam- can guide treatment decisions. Preliminary results point to matory responses have been linked to withdrawal symptoms. lab tests such as lymphocyte, neutrophil, and platelet counts As a result, we hypothesized that microglia, the resident im- as the strongest predictive features for infection, and further mune cell of the central nervous system, serve as a potential exploration is underway to understand the full impact of these target for withdrawal treatment. In order to test this, we re- and other features. duced microglial activity by inhibiting the purinergic signal- ing pathway. This was achieved by first exposing mice to es- calating doses of fentanyl over the course of a few days to cre- SESSION T-2H ate tolerance. Then, we administered clopidogrel, a selective antagonist of the P2Y12 receptors which are expressed in mi- croglia, before inducing withdrawal using naloxone. Subse- COMPUTER SCIENCE & quently, in order to quantify whether inhibition of microglial ENGINEERING P2Y12 receptors mitigated naloxone-precipitated withdrawal 10:05 AM to 10:50 AM in fentanyl-tolerant mice, we measured avoidance of the with- * Note: Titles in order of presentation. drawal context with the conditioned place aversion (CPA) test, and evaluated somatic signs of withdrawal with Etho- Vision video analysis. Avoidance of the negative emotional and physical symptoms of withdrawal is a key driver of re- 2 Nightwatch Connect A Hierarchical Approach to Designing Itsumi Joy Niiyama, Senior, Informatics (Human-Computer Three-Dimensional, Symmetric Protein Assemblies Interaction), Industrial Engineering Radhika R. Dalal, Senior, Biology (Molecular, Cellular & Jaesuk (Jae) Lee, Senior, Human Ctr Design & Engr: Data Developmental), Biochemistry Science Mary Gates Scholar, Undergraduate Research Jacob Donald (Jacob) Chan, Senior, Industrial Engineering Conference Travel Awardee Sarah Park, Senior, Sociology Mentor: David Baker, Biochemistry Mentor: David Hendry, Information School Mentor: Una Nattermann, Biochemistry The goal of this research is to bridge the gap of stereotypes Computational protein design is an emerging field that takes between
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