Health Sciences – Page 22 – UROP Spring Symposium 2021

Health Sciences

Michigan Self-Screening Home Health (MISSH) Study

Cervical cancer is mainly caused by the Human Papillomavirus (HPV) and is easily preventable by performing HPV screenings every five years, a PAP smear every three years, or both every five years for women over the age of 30. While a number of women are getting regularly screened, there are still populations of women who are under-screened because of cultural beliefs, lack of access to screening, the burden of taking time off of work, and other factors. In this study, women from under-screened populations recruited through community partners are sent HPV self-sampling kits to be used at home which include a vaginal sample and a urine sample. The participants are then interviewed over the phone to collect quantitative and qualitative data for the feedback for self-sampling. The study is ongoing and the results are yet to be analyzed. Results from the study can be used to help approve self-sampling HPV testing to be used by physicians and women which will provide women an opportunity to be screened easily and provide access to cervical cancer screening to women in under screened communities and countries.

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Michigan Self-Screening Home Health (MISSH) Study

The Michigan Self-Screening Home Health (MISSH) 2 research project that is being done by the Harper Lab is about research on HPV (human papillomavirus) at-home testing kits that could potentially be the future of cervical cancer screening. Getting screened for cervical cancer is important for many reasons. HPV causes nearly all cases of cervical cancer and there are different strains, including HPV 16 and 18, which are considered high risk for developing into cervical cancer. If women get tested regularly, these strains can be detected early and any issues can be treated before developing into cervical cancer. Traditionally, cervical cancer screening has been done by a doctor using methods such as a Pap Smear, which collects cells from the cervix and looks to see if they show any changes caused by an HPV infection. These tests can feel invasive or not be accessible for many people. To increase cervical cancer screening, the Harper Lab is looking into new HPV self-screening devices that can be used at home without the need to go to the doctor. MISSH is sending volunteers HPV at-home testing kits, participants are either able to choose 1 of the 2 kits or are asked to try both of the testing kits. After using the kits they answer some questions through phone surveys conducted by the MISSH 2 staff in which they are asked how they felt about the kit they chose or which of the 2 kits they preferred. They are also asked if they prefer these testing kits to the standard Pap screening that the Doctor performs. MISSH 2 is still an ongoing project that is still conducting surveys of participants but we hope to see a preference for these at-home testing kits for HPV and see if people would be more willing to get screened for cervical cancer using this method.

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Determining the kinetic parameters of CD39 – an enzyme with multiple substrates and products

Enzyme kinetics are often summarized in the form a Michaelis-Menten type model with parameters representing the maximum velocity of the reaction and concentration of substrate where the reaction is at half of the maximum velocity. Traditionally, these parameters can be experimentally determined by using linear regression between the reciprocal of the rate of reaction and reciprocal of the concentration of substrate (ex: Woolf-Augustinsson-Hofstee plot, Lineweaver-Burk plot) [REFs]. Implicit within these methods is the assumption that the enzyme of interest has a single substrate and single product. For enzymes such as CD39 with multiple substrates and products, these methods are likely inappropriate to accurately determine their Michaelis-Menten parameters. CD39 is an ectonucleotides that can hydrolyze ATP and ADP into ADP and AMP, respectively. In this study, we develop and analyze the behavior of a model of CD39 enzyme kinetics accounting for substrate competition. Simulations with our model using Michaelis-Menten parameters for CD39 ATPase and ADPase activity determined by the Woolf-Augustinsson-Hofstee method do not acutely explain kinetic data of ATP, ADP, and AMP concentrations reported by Kukukski et al. [REF]. Using non-linear parameter estimation, we determine parameters for our CD39 model that accurately capture the kinetic data. Uncertainty in our model predictions is quantified using 95% confidence and prediction intervals.

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Determining the kinetic parameters of CD39 – an enzyme with multiple substrates and products

Enzyme kinetics are often summarized in the form a Michaelis-Menten type model with parameters representing the maximum velocity of the reaction and concentration of substrate where the reaction is at half of the maximum velocity. Traditionally, these parameters can be experimentally determined by using linear regression between the reciprocal of the rate of reaction and reciprocal of the concentration of substrate (ex: Woolf-Augustinsson-Hofstee plot, Lineweaver-Burk plot). Implicit within these methods is the assumption that the enzyme of interest has a single substrate and single product. For enzymes such as CD39 with multiple substrates and products, these methods are likely inappropriate to accurately determine their Michaelis-Menten parameters. CD39 is an ectonucleotides that can hydrolyze ATP and ADP into ADP and AMP, respectively. In this study, we develop and analyze the behavior of a model of CD39 enzyme kinetics accounting for substrate competition. Simulations with our model using Michaelis-Menten parameters for CD39 ATPase and ADPase activity determined by the Woolf-Augustinsson-Hofstee method do not acutely explain kinetic data of ATP, ADP, and AMP concentrations reported by Kukukski et al. Using non-linear parameter estimation, we determine parameters for our CD39 model that accurately capture the kinetic data. Uncertainty in our model predictions is quantified using 95% confidence and prediction intervals.

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Understanding the Regulation of CXCR-2 Ligand Production in 4T1 and 4T07 Cells

4T1 and 4T07 cells found in mouse mammary tumors, having been isolated from the same parental tumor, share a common genetic background. However, 4T1 cells metastasize through neutrophil extracellular traps while 4T07 cells do not. It has been shown that the two cells produce different levels of CXCR-2 ligands in vitro but similar levels of these ligands when cultured in the presence of DHMs (an engineered nucleoprotein material that mimics properties of NETs). We hope to find mutations that are present in the metastatic 4T1 cells but are not present in non-metastatic 4T07 cells. By doing so we hope to better understand the importance of mutated genes in tumor metastasis. The team began analyzing 4T1 transcriptomic data published by the Siegel lab in McGill, and from this data each gene’s relative average intensity in the 4T1 cell genome was identified. Following the data analysis, both 4T1 and 4T07 cells were cultured in different environmental conditions in vitro to examine the relationship between environmental stimulus and the production of chemokines. At the same time, the roles of different receptor signaling pathways were studied in regards to how they intervene in the production of chemokines. The research on signaling pathways focuses on areas including the pathways’ functions, downstream effects and their relations to CXCR-2 ligands production. Because the research is not yet complete, we do not have results about the genetic mutations present solely in 4T1 cells. Our data will mainly come from 2D cell culture of 4T1 and 4T07 cells and we expect to see different environmental conditions and various protein signaling pathways causing different effects on chemokine production.

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Computational Approach to Determining the Properties of Rhodamine-Based pH Sensitive Fluorophores used in Diverse Biomedical Applications

Fluorescent probes are excitable by specific frequencies of light and emit bright visible electromagnetic radiation upon their relaxation to a ground state energy. These probes can be chemically modified to tune their properties and impart specific reactivity. In the biomedical sciences, fluorescent probes are widely used in applications including determining the presence and quantity of a specific protein, determining enzyme activity in real-time assays, determining gene expression, and elucidating physicochemical conditions both intracellularly and extracellularly. However, current probes present a significantly high cost, modest fluorescent intensity, and lack chemical functionality for important uses such as site-specific protein labelling, orthogonal click chemistry, and for use in biomaterial constructs. In this study, we aimed at designing high fluorescent yield, tunable pH-sensitive probes which could be synthesized using inexpensive common reagents to illuminate microenvironmental changes in pH, a critical factor in biologic processes including endosomal uptake, lysosome processing, and extracellular matrix resorption.

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Active for Life with chronic obstructive pulmonary disease (COPD)

COPD is a chronic lung-based disease that blocks airflow making it harder to breathe. Studies have also shown that muscle strength in people with COPD is lower than that of age-matched individuals without COPD. The decrease in muscle strength can impede individuals from partaking in physical activity (PA) which has been associated with a slower decline in lung function and reduced hospitalization in people with COPD. Traditional interventions for COPD have focused on moderate to vigorous physical activity (MVPA) but the Active For Life: COPD intervention program designed by Dr. Larson is novel in its emphasis on light physical activity (LPA) and decreased sedentary time. Participants were recruited and sorted into control or experimental groups, followed by 10 weeks of training classes for both groups. The experimental group did functional circuit training and learned self-regulation strategies. The control group did chair exercises and guided imagery for relaxation and health education. Both groups came back at 2 months, 3 months, 6 months, and 12 months to have various measures of strength, endurance, and physical activity tested. A study was undertaken to see the impact of this intervention on isometric strength measures through knee flexors and extensors. Due to the study being ongoing and having a partially blind setup in order to minimize bias, blinded group interim analysis will be analyzed. If this intervention is successful, in increasing physical activity and muscle strength it could change general physical activity guidelines for people with COPD shifting away from MVPA and towards LPA.

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Active for Life with chronic obstructive pulmonary disease (COPD): Physical activity and anxiety

Individuals with Chronic Obstructive Pulmonary Disease (COPD), tend to live a sedentary life which can increase the risk of mortality and heighten symptoms of COPD. In attempting to prevent this sedentary lifestyle in COPD patients, many exercise programs focus on vigorous physical activity which is not sustainable in the long run. The Principal Investigator of this study, Janet Larson, developed an exercise program, called Active Life. The Active Life program emphasizes light physical activity for patients with COPD. The study conducted is a randomized controlled clinical trial where COPD participants are randomly placed into two groups, the Active for Life intervention and the control intervention. The study is conducted to determine if the Active Life intervention is an effective program in promoting physical activity in COPD patients. The participants in the Active Life intervention complete an exercise program including functional circuit training (FCT), health education, and self-regulation strategies. The participants in the control group complete an exercise program that includes chair exercises, relaxation promotion, and health education. The participants complete 10 weeks of lab-based exercise, then a one-year follow-up which measures activity levels and home-based exercises. Through the data collected from the Active Life study, I decided to look into the effect that physical activity has on anxiety levels in patients with moderate to severe COPD. In the study, data was collected on anxiety levels throughout the study as well as different measurements of physical fitness and activity. I examined the long-term (52-week post-intervention) impact of light physical activity on self-reported anxiety compared to the control group.

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Mitochondrial trafficking is altered in insulin receptor knockout dorsal root ganglion sensory neurons

Diabetes is a global epidemic that affects 463 million individuals. Approximately 50% of diabetic patients develop a serious complication called diabetic neuropathy (DN) that can also develop in patients with pre-diabetes and obesity. DN is characterized by tingling or burning, sharp pains, and eventual loss of sensation in the hands or feet that results from significant nerve damage. Despite the severity of DN, there are no disease-modifying treatments for DN associated with type 2 diabetes, prediabetes, or obesity. Recent studies indicate that dyslipidemia correlates with DN, suggesting that fatty acids may contribute to DN onset or progression. Dorsal root ganglion (DRG) neurons are a cluster of primary sensory neurons located just outside the spinal cord that extend axons into the nerves and transmit sensory information from the peripheral nervous system to the central nervous system. DRG neurons depend on mitochondrial trafficking and function to produce ATP in the axons, and it has been reported that insulin signaling regulates mitochondrial function. In this study, we sought to determine whether the presence of the insulin receptor regulates axonal mitochondrial trafficking in fatty acid-treated DRG neurons. DRG neurons from insulin receptor knockout mice (IRKO) were given six different treatments to explore the effect of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs) on axonal mitochondrial trafficking. A kymographing analysis was used to analyze mitochondrial transport in individual DRG axons and identify the percent of mitochondria that were stationary or motile. Interestingly, we found significantly fewer motile mitochondria in the IRKO DRG axons compared to wild type DRG axons. The SFA treatments impaired mitochondrial trafficking, while the addition of MUFAs prevented the reduction in mitochondrial trafficking in both wild type and IRKO DRG neurons. This study suggests that the loss of the insulin receptor reduces basal mitochondrial trafficking in DRG neurons but does not contribute to fatty acid-induced alterations in mitochondrial trafficking.

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Effect of aging on human induced pluripotent stem cell generation

Coronary stents are used to relieve patient symptoms of angina, or chest pain, due to obstruction of blood flow in coronary arteries. After stents are implanted, endothelial cells grow over the stents. Before that occurs, patients are at risk for developing a clot, or thrombus, inside of the stent. We are seeking to find novel ways to accelerate the coronary stent endothelialization process. We aim to understand if human-induced pluripotent stem cells (hiPSC-ECs) are a viable option for pre-endothelializing stents prior to implantation. In addition to aiming to determine stent growth properties on coronary stents, we aim to discover if there is a phenotypic difference between the endothelial cells created from hiPSC-ECs taken from younger and older patients by using a sample of their mononuclear blood cells. We are currently taking blood samples from older subjects having a procedure in the cardiac catheterization lab. After obtaining consent for the patient, approximately 8 mL of the patient’s blood is drawn from the patient’s IV into a vial with an anticoagulant. The vial is centrifuged for 30 minutes at 1800 RCF in order to isolate the mononuclear blood cells. Afterward, the sample is transported to the Cardiovascular Regeneration Core Laboratory, where the cells are converted to hiPSC-ECs and placed on commercially-available coronary artery stents to observe their growth. Thus far, one blood sample has been recently collected, with results from the cardiovascular regeneration core lab pending. Separately, subjects in the young age group will be recruited through the www.UMHealthResearch.org website. In total, we aim to test cells from blood samples acquired from 20 different patients over the course of the year. Potentially, hiPSC-ECs from older patients can be reprogrammed to more closely resemble cells from younger patients.

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