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.
Anne Schaar, PhD
(Faculty Mentor – Rozalyn Anderson, PhD)
“Targeting the AMPK/PGC1a axis to improve muscle energy metabolism and offset age-related muscle mass and function loss.”
My work primarily investigates the metabolic and functional changes in skeletal muscle due to aging, termed sarcopenia. Previous work by the Anderson lab in nonhuman primates show that age-related declines in mitochondrial energy metabolism, cellular redox, and lipid storage anticipate the onset of sarcopenia and occurs in advance of physical activity decline and frailty. Adiponectin is an adipokine known to influence skeletal muscle cellular metabolism by activating lipid utilization and mitochondrial oxidative pathways. My research utilizes an adiponectin receptor agonist to investigate whether altering the AMPK/PGC1a axis can improve muscle energy metabolism and subsequently offset the effects of sarcopenia in aged mice.
Current Predoctoral Trainees
(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.
(Faculty Mentor – David Wassarman, PhD)
“The Role of Aging-dependent Metabolic Dysfunction in Traumatic Brain Injury Outcomes”
Traumatic Brain Injury (TBI) is predicted to be the 3rd leading cause of death worldwide by 2020, with 50,000 victims dying each year in the United States and thousands more survivors suffering from long-term disabilities, making it one of the greatest public health burdens in society today. Elderly populations in particular are highly vulnerable to the effects of TBI, resulting in higher rates of mortality, and severe cognitive and emotional deficits in survivors. My work in the Wassarman lab utilizes our Drosophila melanogaster model of TBI to characterize how aging affects the metabolic state of flies immediately following TBI, as well as to elucidate the mechanisms that lead to disrupted energy homeostasis and ultimate TBI outcomes. These studies will provide a better understanding of the critical genes involved in metabolic dysfunction following TBI, establish where the most severe dysregulation is taking place, and identify novel targets for metabolic therapies.