Grant Program: New Investigator Program

Atrial fibrillation (AF) is an abnormal heart rhythm that can increase a person’s risk for heart failure and stroke. While strategies for preventing these complications exist, less work has been done on a cure. This project sought to understand the mechanisms behind AF, with the goal of informing new therapies and improving patient outcomes. The researchers gained crucial knowledge and understanding about the mechanisms contributing to AF by successfully completing all proposed experiments. These experiments included engineering a human cardiac tissue model, identifying novel potential targets for pharmacological treatment against AF, and understanding what plays a role in the protection of the heart against pathological changes in the settings of chronically elevated blood pressure. This project was successful in increasing knowledge, fostering collaborations, publications, and developing new funding opportunities.

In Wisconsin, 750,000 people live with diabetes, and 25 percent of those individuals will develop a diabetic foot ulcer (DFU), a common complication of diabetes, in their lifetime. DFUs can remain open for a long time, and it can be difficult to predict which of these wounds will respond to treatment and heal or require amputation. Wound tissue supports the colonization of a diverse community of microbes referred to as a microbiome. The microbiome in the wound tissue is thought to sustain inflammation which impairs healing and tissue repair. There is a critical, unmet need to develop methods that predict if diabetic wounds will heal in response to treatment, or if they will remain open and healing will be stalled due to a complex microbiome. In this study, researchers hypothesized that the wound microbiome interacts with host healing pathways and genes that control tissue repair. Ultimately, they found that anaerobic bacteria species, which can survive and grow with no oxygen, are more abundant and transcriptionally active in the microbiome of persistent and amputated wounds. Therefore, anaerobic bacteria may serve as a predictive biomarker of wound healing. The research team has received a $26,000 Wisconsin Alumni Research Foundation (WARF) Technology Accelerator Grant and a $2 million NIH grant to expand their work.

Lupus — an autoimmune disease that causes inflammation and organ damage — disproportionately affects patients of color and those of low socioeconomic status, who also experience higher rates of associated kidney disease and early death. Ensuring that patients get regular care could help keep symptoms in check, but retention predictors in lupus care are poorly understood. This study defined retention in care for different demographic groups in Wisconsin, finding that those from the most disadvantaged neighborhoods were the most at-risk of ~60% lower retention in care. The insights generated from this research have the potential to help providers reduce lupus outcome disparities in the future.

Studies have implicated the failure of proper chromosome segregation, a process that is critical for cell proliferation and for maintaining life in all organisms, in both cancer and birth defects. This project explored the scientific premise that the kinetochore, a protein structure that forms during cell division, ensures proper chromosome segregation and prevents errors in mitosis. This project provided fundamental insights into cancer and developmental diseases by yielding new understanding of kinetochore functions. Through the work completed during this grant period, the researchers were able to make progress on developing a novel super-resolution imaging methodology which is not only well-suited to studying kinetochore dysfunction, but also can be utilized for broad research fields.

Heart failure continues to be a major health issue in the United States, characterized by 6 million adults affected in the years 2015-2018, according to the American Heart Association. Ischemic injury is caused by the absence of or diminished flow of blood, which can lead to heart disease and heart failure that affects the function of the heart by reducing its ability to pump blood effectively. This project explored new strategies to repair the adult human heart following injury caused by heart disease, which can cause irreversible loss of part of the heart muscle. The research team identified mechanisms that occur in heart regeneration in newborns that could be applied to adult hearts in order to aid in cardiac regeneration. These data support the possibility of people regaining cardiac function after injury.

Diabetes affects almost 600,000 people in Wisconsin and costs state residents $6.15 billion per year, numbers which are expected to triple in the next 15 years. Type 2 diabetes (T2D) accounts for the majority of these cases and is linked to the failure of insulin secretion from pancreatic β-cells (beta cells) that keep blood sugar in check. These rapidly climbing number pose a significant burden on the healthcare system. The researchers identified a new potential target for diabetes therapy, the metabolic enzyme pyruvate kinase (PK), which has been found to be sufficient in initiating and amplifying insulin secretion. Their work suggests that PK activation could be utilized to promote the healthy metabolic function of β-cells in order to prevent or reduce T2D.

As people get older, stems cells in their brains age with them, which can contribute to age-related diseases. However, the mechanisms underlying stem cell aging aren’t yet completely understood. This work seeks to better understand the processes by which neural stem cells decline, with the goal of improving health for senior citizens. The researchers found that although the role of nesprin-3 remains elusive; this study produced more knowledge that had not previously been shown in the research. The lab’s use of data and extensive controls revealed that the available tools for this research are not sufficient for this investigation and not functioning as were reported. This knowledge will inform future work.

Each year, around 11 million people worldwide sustain burn injuries severe enough to require medical attention. One year in Wisconsin contributes 61 fatalities and over 600 hospitalizations related to burn injuries to the worldwide total. Burn survivors can experience lifelong pain, scarring, and infection from burns as well as from the surgery needed to heal the wounds. As such, there is a significant need to develop new treatment strategies. This work aims to understand how healing can be accomplished without grafting healthy skin from the patient’s body. The research team met the overall goals of this project, which included developing and characterizing an ex vivo (outside of an organism) human burn injury model, including instrumentation to generate consistent and reliable thermal injury identification of the natural variation in human skin, and the ability of the tissue to recover in culture.

Most older women in Wisconsin experience incontinence, which impacts quality of life, but they may not seek care due to stigma. The “Mind over Matter: Healthy Bowels, Healthy Bladder (MOM)” workshop teaches women skills to improve symptoms without a medical professional. Participants in the MOM workshop reported significant improvement in both bladder and bowel symptoms. Since the trial, more than a dozen additional MOM workshops have taken place and more widespread workshops and trainings are planned for 2020, in partnership with the Wisconsin Institute for Healthy Aging (www.wihealthyaging.org).

The human immune system plays a critical role in maintaining health by preventing autoimmunity, infection, and cancer. Because of the significant differences in immune function between individuals, past research aiming at generalized strategies for all individuals has failed to provide satisfactory treatments for these diseases. This project, led by Yun Liang PhD, Department of Medical Microbiology and Immunology and collaborator Shivani Garg, MD, Department of Medicine, is designed to address the urgent need to develop novel approaches for immune-associated diseases by advancing the scientific understanding of the molecular basis of immune variations. Such understanding may lead to novel, molecular targets for the treatment of autoimmunity, infection, and cancer. In addition, the researchers will work to advance health equity by addressing the therapeutic needs of historically underserved populations including women and populations of low socioeconomic status.