Grant Program: New Investigator Program

This project, led by Dr. Ivan Rosado Mendez, aimed to develop and implement ultrasound microvessel imaging (UMI) as a functional imaging technique to study cervical remodeling during pregnancy in real time. Cervical remodeling describes the progressive changes of the cervix during pregnancy and involves four phases: softening, ripening, dilation and postpartum repair. If the cervix ripens in preparation for delivery too early, it can cause premature birth. Preterm birth (PTB), defined as delivery before 37 weeks of pregnancy, results in one million deaths worldwide and is associated with significant racial and socioeconomic disparities. The researchers successfully developed a cervical tissue-mimicking model, called a phantom, composed of agar-based simulated tissue, fluid-carrying channels, blood-mimicking fluid and a system to control fluid dynamics. They validated channel dimensions with micro-CT scans, ensured stability over 14 days and selected a fluid that best matched the features of human blood for the prototype. Finally, the team implemented a high-resolution imaging protocol that was able to detect fluid movement through the channels even when surrounded by simulated tissue.

Humans rely heavily on vision, primarily facilitated by cone photoreceptors in the macula, which provide high-definition spatial and chromatic resolution. Macular degeneration, a leading cause of blindness, affects about 20 percent of people over 45 in Wisconsin. Recent advances in human pluripotent stem cell (hPSC) engineering have made it possible to create 3D retinal organoids (ROs) that mimic the retina’s structure but have yet to demonstrate the phototransduction needed for vision. The goal of this project was to demonstrate that cone cells in lab-grown ROs can respond to light like those in a healthy human eye and test gene therapies to restore vision in patients with achromatopsia. The researchers found that cells in lab-grown ROs had slower and less sensitive responses compared to those in mature primate eyes and confirmed the immaturity of the ROs through 3D mapping of cell connections. The lack of a retinal pigment epithelial (RPE) layer, essential for recycling vision pigments, resulted in limited light sensitivity, but adding artificial pigments improved the cells’ response to light. Using stem cells from achromatopsia patients, the team created ROs that mimicked the condition and they are now testing nanoinjection for delivery of gene therapy after unsuccessful attempts with viral vectors. Overall, this project has made significant strides in understanding and improving lab-grown retinal cells’ function.

This project, led by Matthew Harer, MD, associate professor, Department of Pediatrics, aimed to enhance early acute kidney injury (AKI) diagnosis in premature infants via non-invasive methods. AKI is prevalent among premature infants and it significantly increases mortality and poses a risk of chronic kidney disease (CKD) later in life. In Wisconsin, about 800 extremely premature infants are born each year, with up to 400 experiencing AKI and approximately 100 potentially developing CKD by ages two to five years old. As a result, there is a need for novel diagnostic methods to identify AKI in the NICU. The research team made significant progress toward its goals of enhancing early AKI diagnosis and developing effective therapies. They found that infants with AKI experienced prolonged periods of kidney hypoxia and that administering caffeine improved kidney oxygen levels. Additionally, urinary biomarker analysis identified distinct metabolite profiles associated with AKI, suggesting potential for early diagnosis and intervention in preterm infants to avoid chronic kidney disease. More research is needed, but these findings laid a foundation for improving care and outcomes for premature infants at risk of AKI.

The Vascular Effects of the Precision Interventions for Severe Asthma (VASC-PreCISE) led by Matthew Tattersall, DO, MS, associate professor, Department of Medicine, aimed to investigate biomarker-guided treatments for asthma and their impact on arterial injury and cardiovascular risk, focusing on improving blood vessel function and reducing inflammation through novel therapies. Asthma affects over 500,000 individuals in Wisconsin, with higher hospitalization and mortality rates among ethnic minorities. Certain asthma types, particularly persistent or late-onset forms, are linked to increased cardiovascular disease (CVD) risk due to shared inflammatory pathways. This connection represents a knowledge gap and a need for targeted approaches in treating both asthma and CVD. The VASC-PreCISE successfully enrolled 25 participants and collected 75 blood serum samples along with 75 ultrasound scans of participants’ carotid and brachial arteries to evaluate blood vessel health and inflammation. Data analysis was scheduled for February 2024 post-randomization to maintain trial integrity. Ultimately, this project fostered partnerships and led to a KL2 Scholar Award to continue research on precision asthma anti-inflammatory therapies.

The goal of this project was to increase compliance in postpartum care among Black women by incorporating community partnerships into the “Staying Healthy After Childbirth” (STAC) care model, which is a telehealth hypertension management program offered by UnityPoint Health-Meriter. Hypertension disorders affect around 22 percent of pregnancies in Wisconsin, with preeclampsia and eclampsia being 60 percent more common and substantially more severe in Black women than white women. While the American Congress of Obstetricians and Gynecologists recommends early outpatient follow-up for postpartum women with hypertension disorders, up to 40 percent do not attend. Initial data from the STAC program showed that it was successful in obtaining blood pressure readings from 94 percent of women, compared to 60 percent in standard follow-up, however, compliance with remote blood pressure monitoring varied 23 percent between Black and white women. The project successfully enrolled 48 out of 55 planned participants and integrated community-based, racially concordant doulas into their postpartum care. Preliminary findings revealed a significant improvement in health care engagement for Black mothers with doula support, as evidenced by their total blood pressure readings during the 42-day postpartum period. Qualitative feedback from study participants emphasized the program’s live-saving impact, particularly in postpartum recovery and medication management, with emotional support from doulas contributing to positive well-being and overall experience.

Down syndrome, also known as trisomy 21, is a condition that impacts the brain’s development of neurological pathways resulting in mild to moderate intellectual disability and middle age onset of Alzheimer’s disease. Basal forebrain cholinergic neurons (BFCNs) are crucial in mediating cognitive performance and memory throughout the lifespan, and they are particularly susceptible to degeneration in individuals with Down syndrome. This project sought to explore the mechanisms that underlie BFCN vulnerability in Down syndrome and looked specifically for observable and age-related markers of BFCN dysfunction in trisomy 21. The results showed similar levels of Alzheimer’s-related proteins in the BFCNs of individuals with and without Down syndrome, despite the fact that people with the condition have an extra gene copy that produces these proteins. The research team identified that trisomy 21 BFCNs had elevated levels of aging markers which may contribute to the intellectual disability and middle age onset of Alzheimer’s disease in people with the condition.

There are 7,000 different rare genetic disorders that impact approximately 450,000 people in Wisconsin. Gene therapy has the potential to treat these diseases if two major limitations can be addressed: better targeting of the therapy agent and affordability. This project, led by Kinjal Majumder, PhD, assistant professor, Department of Oncology, seeks to address these limitations by improving the nuclear targeting of gene therapy vectors. The team will use a combination of CRISPR/Cas9 technology, Big Data and high-resolution imaging to study the molecular mechanisms of Recombinant Adeno-Associate Virus (rAAV) vectors for gene therapy delivery and provide insights into engineering better rAAV gene therapy vehicles. Their findings will inform future studies and collaborations in the field of gene therapy, with the potential to improve treatments for rare genetic disorders and develop cancer-targeting gene therapies.

Birth Cost Recovery (BCR) holds unmarried, non-custodial fathers liable for Medicaid birth costs in Wisconsin, yet there is little known about the impact of this policy on Black birthing people in Wisconsin. This project, led by Tiffany Green, PhD, assistant professor in the departments of Population Health Sciences and Obstetrics and Gynecology, will work to better understand how BCR and other similar social policies impact inequities in health outcomes among low-income Black birthing people in the state of Wisconsin. Dr. Green and a team of interdisciplinary experts in the fields of economics, population health, pediatrics, social work, clinical/social psychology and community engagement will create an evaluation framework for BCR as a way of measuring the impact of this policy and collect evidence that can be useful in informing future policies and improving health outcomes statewide.

This project, led by Dr. Jasmine Zapata, aimed to evaluate the feasibility and preliminary outcomes of the Today Not Tomorrow Pregnancy and Infant-Support Program (TNT-PISP). TNT-PISP is a collaborative community-based prenatal care and support group in Dane County that was uniquely designed to serve Black women and infants. Wisconsin’s Black infant mortality rate is the highest in the nation and there is increasing evidence that models of prenatal care that are community-driven, group-based, culturally-relevant and family-centered have the potential to significantly improve maternal and infant health outcomes. The TNT-PISP generated significant short-, medium- and long-term impacts. The program provided valuable peer support and resources for Black mothers, with 98 percent of participants sharing that they would be willing to return. Thematic analyses highlighted positive effects of the program, including providing peer support, a safe space for Black mothers to share their experiences and valuable information about resources for parents, breastfeeding and community-based doula programs.

In Wisconsin, one in three older adults is admitted to an intensive care unit (ICU) at or near the end of their life despite the vast majority expressing preferences to avoid such care. Patients in the ICU are often too sick to speak for themselves, and family members are asked to make these difficult decisions on the patient’s behalf. As a result of these challenges, surviving family members experience psychological distress after the patients’ ICU stay and ICU clinicians experience moral distress and burnout. Previous efforts to improve end-of-life ICU care have utilized time-limited trials which are agreements among patients, their surrogate decision makers, and clinicians to attempt life-sustaining treatment for a predefined period before evaluating whether the treatment is helping the patient. The specific objective of this project is to optimize the time-limited trial model to meet the needs of older adults admitted to the ICU and their surrogate decision makers. Successful completion of this project will determine whether the time-limited trial model of care leads to better end-of-life outcomes for patients, families, and clinicians.