Graduate Students

Spring 2017

Jordan Anderson (Duke University)
The Effects of Early Adversity on T-cell Receptor Diversity in Wild Baboons

The experience of adversity during early life can powerfully shape an organism’s life course. For example, in humans, low early life socioeconomic status (SES) predicts increased rates of heart disease, even in individuals who later attain high SES. Early life adversity also predicts longevity in other animals, suggesting that some responses to early life insults are rooted in our evolutionary history. The “extrinsic mortality cue” hypothesis proposes that early life adversity serves as a cue for a harsh external environment, which predicts a shorter life and selects for reduced investment in specific immune defenses (e.g. those that defend against specific pathogen strains). I propose to test this hypothesis using a recently developed genomic method for characterizing T-cell receptor (TCR) diversity, an important component of recognizing and responding to individual pathogens. To do so, I will take advantage of a long-term study population of wild baboons in which both genomic data and extensive information on early life experiences are available and early adversity has been shown to predict higher mortality rates. I predict that early adversity will be linked to reduced TCR diversity, reflecting a reduction in specific immune defenses. By focusing on a primate that is closely related to humans, my results will further our understanding of the evolutionary and biological mechanisms linking early adversity to later life health.

Jeremy Ash (North Carolina State University)
Using Molecular Modeling and Machine Learning to Study Dynamic ERK-ligand Interactions
Kinase inhibitors represent the new generation of highly promising bioactive molecules for combating various types of cancer. With compounds already on the market and even more currently in clinical trials, the research community is on the path to developing a large collection of kinase-mediating drugs and chemical probes. However, drug resistance is the “Achilles heel” of kinases inhibitors. As members of signaling pathways that are critical to an array of cellular processes, kinase inhibition gives rise to strong selection pressure for drug resistance conferring mutations in patients. In this project, we focus on studying the ERK1 and ERK2 kinase, especially the dynamic interactions small molecule inhibitors undergo within the ERK binding site. To do so, we will rely on our novel modeling approach that integrates several state-of-the-art cheminformatics methods (molecular docking, molecular dynamics, and machine learning). We posit this analysis will deepen the understanding of why certain inhibitors interact differently with these two isoforms. This will help identify residues where the selection pressure driving drug resistance is different, and inform chemists of strategies to design new ERK inhibitors with greater efficacy. At last, our analysis of ERK-ligand dynamic interactions that confer specificity to ERK1, ERK2, or both will aide in the development of new chemical probes capable of more selective

Katie Barrett (University of North Carolina, Chapel Hill)
The Developmental Roles of Leptin and Ghrelin: Mammalian Comparisons
Human metabolism is programmed during the gestation and the first two years of postnatal life. The reasons for this are rooted in our evolutionary history. This metabolic programming influences our risk of obesity and other chronic diseases, and the hormones leptin and ghrelin may play an important role both in our early development and later disease risk. Our understanding of the roles of leptin and ghrelin in human appetites and disease risk are constantly improving, but there is still a need to understand how our evolutionary history has influenced those roles. This project will compare studies in rodents and non-human primates with human studies in order to explore how human evolution and the roles of leptin and ghrelin in human development may be linked.

Nicholas Brazeau (University of North Carolina, Chapel Hill)
The Evolutionary Origins and Global Dispersal of Plasmodium vivax
Malaria in humans is caused by several different parasites. One in particular, Plasmodium vivax, is believed to have evolved in African non-human apes prior to the parasite making the zoonotic leap and infecting their closest cousin, us! Humans then transported the parasite to Asia and Latin America, where today the disease afflicts millions. Although originating in central Africa, vivax malaria has been considered absent in these areas due to the high prevalence of a mutation that confers the Duffy-negative phenotype, offering protection against P. vivax infection. However, recent evidence has begun to ove rturn this view, as P. vivax has been found in several African countries among individuals with the supposed protective mutation. Through a large, representative population study of the Democratic Republic of the Congo, our group h as identified several P. vivax cases infecting Duffy-negative (“protected”) individuals. I am studying these new cases to determine what has caused their reemergence and their evolutionary origins by comparing them to the potentially ancestral African non-human ape sequences. Determining the evolutionary origins of P. vivax will help us to better understand drug resistance and to devise better malaria control and elimination interventions.