Current Postdoctoral Trainees
Hannah Foster, PhD
Faculty Mentor- Matthew Merrins, PhD
“Pyruvate kinase activators as a therapy for Diabetes II in elderly patients”
The pancreatic islets of Langerhans are known for their ability to couple metabolic glucose sensing with appropriate insulin secretion. This coupling is crucial for the maintenance of blood glucose levels, and failure of this system leads to metabolic diseases—most notably, Type II Diabetes, which afflicts more than 25% of people over the age of 65. Current therapies to treat diabetes in seniors, such as GLP1 agonists, have limited efficacy versus in younger adults, driving us to explore new potential therapies. This led us to pyruvate kinase (PK), the protein responsible for catalyzing the final step in the glycolytic pathway, and small-molecule PK activators. I have tested PK activators on islets from both sexes and across all ages and found efficacy in increasing insulin secretion in all populations, including the elderly. My current research continues to explore the role of PK and the effects of PK activators in healthy and diseased islets using several mouse models and donated young and aged human islets with the goal of deepening our understanding of the insulin secretory system and how it changes throughout the human lifetime.
Jeremy Kratz, MD
Faculty Mentor- Dustin Deming, MD
“Organotypic Cultures to Characterize Heterogenity of Therapeutic Response in Geriatric Oncology”
My research investigates techniques for developing translational tools to advance the practice of precision oncology for geriatric patients with gastrointestinal cancers. The goal of my work is to develop techniques as a correlative biomarker to predict response for an individual patient. Geriatric patients represent 15% of those enrolled in prospective oncology studies while accounting for 70% of cancer-related mortality. Tuning therapies with improved therapeutic activity is necessary to avoid added toxicities from ineffective therapies. This includes prospective investigations of cancer spheroids assessed by change in growth and metabolism from the University of Wisconsin’s Precision Medicine Molecular Tumor Board.
Yuetiva Robles, PhD
Faculty Mentors – Barbara Bendlin, PhD and Corinne Engelman, PhD
“Unraveling the underlying biology of Alzheimer’s pathology with big-data ‘omics”
The foundation of my research is analysis of genetic associations with quantitative traits, such as disease biomarkers and endophenotypes, to help further our understanding of complex disease. Currently my research integrates genomics, proteomics, metabolomics, and bioinformatics methods to help determine the underlying biology impacting Alzheimer’s disease (AD). By focusing on biological mechanisms rather than clinical diagnosis, my research will not only help in understanding AD pathology but also in understanding disorders that share some of the same biological mechanisms. With greater understanding of the underlying biological mechanisms of disease, we can begin to explore therapeutic targets.
Yang Yeh, PhD
Faculty Mentor – Dudley Lamming, PhD
“Selective protein restriction as a late-life dietary intervention for healthspan, lifespan, and senescence”
I am interested in dissecting the biological mechanisms of aging in order to identify novel life-extending therapeutics. Caloric restriction (CR) remains the most robust mean of improving longevity but its compliance is difficult in humans. The dietary reduction of branch chained amino acids (BCAAs), especially isoleucine (Ile), confers many benefits of CR when fed lifelong. My research will evaluate whether the BCAA- or the Ile-restricted diets can serve as a late-life intervention in aged animals. Further, recent advances with senolytic drugs have entered the clinical stage as a new wave of life-extending treatments with potential benefits in improve dementia symptoms. My work will also evaluate whether the effects of protein-restriction share any common mechanisms with these anti-senescent drugs.
Current Predoctoral Trainees
Faculty Mentor – Miriam Shelef, MD, PhD
“Defining rheumatoid factor’s role to better understand and treat rheumatoid arthritis and other diseases that affect the aging population”
Rheumatoid arthritis (RA) is a chronic, inflammatory disorder involving pain, stiffness and swelling of the synovial joints that can lead to decreased performance in activities of daily living and decreased productivity in the aging population. Most patients with RA have rheumatoid factor (RF), antibodies against the Fc portion of IgG. RF positivity is a poor prognostic marker in patients with elderly onset RA, underlining a potential pathologic role. My project involves identifying novel sites of binding by RF, which may provide insight into the currently unknown pathology of rheumatoid arthritis. Further, by evaluating RF reactivity in rheumatoid arthritis and control subjects, we will support the development of improved RF-based diagnostic tests. This will benefit the aging population as rheumatoid arthritis is among the most common inflammatory diseases in older age groups. The inflammatory pathway in rheumatoid arthritis may also provide insights into inflammation in other autoimmune and infectious diseases.
Faculty Mentor – Lingjun Li, PhD
“Mass Spectrometry-Based Metabolomics for Alzheimer’s Disease Biomarker Discovery”
Alzheimer’s Disease (AD) is the sixth leading cause of death in the United States and is the most common cause of dementia in the aging population. In order to diagnose AD prior to cognitive symptom onset, the complete metabolome and lipidome of AD must be well-characterized, and there is a need to develop better technology to allow for detection of early AD markers with greater sensitivity and accuracy. Typically, AD metabolomic studies utilize brain tissue, cerebrospinal fluid (CSF), plasma, and serum as tissue sources, but my research focuses on erythrocytes, or red blood cells. Erythrocytes are an overlooked component of blood and are a valuable source of disease biomarkers, as erythrocytes are active metabolic cells with intact biochemical pathways that are maintained throughout the cell’s lifespan. Because of this, any changes in red blood cell metabolite concentrations in AD patients could be indicative of systemic metabolic dysfunction, which could give insight into the systematic progression of AD. In my research, I use mass spectrometry to detect and quantify metabolites and lipids in AD erythrocytes.
Faculty Mentor – Luigi Puglielli, MD, PhD
“Structural and translational properties of the resident endoplasmic reticulum acetyltransferases”
Autophagy is an essential component of the cell degrading machinery. It helps dispose of large toxic protein aggregates that form within the secretory pathway and in the cytosol. Malfunction of autophagy and disruption of proteostasis contributes to the progression of many chronic diseases, including neurodegeneration, cancer, nephropathies, immune and cardiovascular diseases; and has been implicated with aging. ATase1 and ATase2 are components of the endoplasmic reticulum (ER) acetylation machinery which transfer acetyl from acetyl-coenzyme A (CoA) onto newly generated, properly folded proteins. Biochemical inhibition of the ATases has been shown to rescue both a progeria-like and an AD-like phenotype in relevant mouse models. The aim of my work is to characterize the structural and biochemical properties of ATase1 and ATase2, which will help us dissect important molecular aspects of the ER acetylation machinery and identify novel compounds for translational application in the fields aging and AD.
Taylor Schoen, MS
Faculty Mentors – Anna Huttenlocher, MD and Nancy Keller, PhD
“Investigating longevity factors as targets of antifungal development”
Aspergillus fumigatus is the primary causative agent of invasive aspergillosis, a devastating fungal disease which primarily affects immunocompromised populations. Canonical regulators of eukaryote longevity such as NAD+ metabolism and sirtuins are conserved in A. fumigatus, however, the role of aging pathways in virulence of this human pathogen remains unknown. The goal of my work is to dissect how metabolic pathways important to longevity drive virulence of A. fumigatus and how those pathways can be targeted to improve antifungal therapies. This work will provide us with a better understanding of the role of aging and metabolism at the host-pathogen interface and allow identification of targetable fungal pathways to treat invasive aspergillosis.
Faculty Mentor – David Pagliarini, PhD
“Defining the biochemical mechanisms of early-stage complex I assembly”
Mitochondria lie at the heart of cellular metabolism, using the oxidative phosphorylation (OXPHOS) system to generate ATP as a cellular energy source. OXPHOS dysfunction has been linked to a wide spectrum of clinical diseases, including disease of aging (e.g. Alzheimer’s disease, type 2 diabetes mellitus). OXPHOS dysfunction is most commonly caused by defects in complex I (CI) of the respiratory chain. While the mature complex has been studied extensively, only a third of CI dysfunctions are due to mutations in its structural subunits. The remaining two thirds are caused by mutations in proteins involved in the assembly and maturation of CI, which are collectively termed “assembly factors (AFs).” To date, 16 AFs have been identified, but the biochemistry underlying their function remains poorly defined. My research interest lies in elucidating the biochemical mechanisms of CI assembly, beginning with the initial stages of assembly. A deeper understanding of this process will advance our knowledge of mitochondrial metabolism as a key player in aging and age-related disease vulnerability.