Summer Scholars Program

Background: One in three older adults fall every year, leading to fractures, disability, and loss of independence. Our work has shown that physical, cognitive, and psychosocial fall risk domains predict recurrent falls among older adults. However, it is less clear whether certain fall risk assessments are more predictive than others. In addition, risk factors are typically examined at a single time point, but growing evidence suggests that there is day-to-day variability in risk factors including gait, balance, physical activity, sedentary behavior, and sleep. Challenges to measuring fall risk factors at multiple time points include time constraints and costs associated with traveling to in-person lab assessments. Advancements in technology, such as mobile health and activity monitors, offer innovative solutions to measuring fall risk factors remotely over multiple days.

Purpose: The objective of this study is to 1) identify physical, cognitive, and psychosocial factors that are associated with future falls over 6-months in older adults with impaired mobility; and 2) examine whether variability in physical function is associated with future falls over 6-months in older adults with impaired mobility.

Methods: Dr. Hsieh (Georgia State University) and Dr. Jehu (Augusta University) will combine their expertise in technology, aging, and falls prevention to lead the proposed study. A total of 80 older adults with impaired mobility (n=40 at each site) will complete a baseline visit of physical performance, cognitive, and psychosocial assessments. Participants will then complete mobility tasks on a smartphone and wear an activity monitor for one week. Falls will be tracked on falls calendars or via incident reports from medical records over six months.

Implications: Results of this study will identify predictors of falls and may have implications for future screening and targeted interventions for older adults with impaired mobility.

IRB: GSU is the IRB of record on this joint project. The IRB application for this project is approved (IRB ID: H24021).

Chronic kidney disease (CKD) poses a significant complication for cancer patients undergoing cisplatin-based chemotherapy. Recently, through the application of a novel intermolecular ligation and transcriptome-wide sequencing strategy, we identified direct pairs of microRNAs and their target messenger RNAs (mRNAs) in cisplatin-injured chronic kidney tissue. This research unveiled a subset of cisplatin-induced microRNAs capable of targeting specific mRNAs, influencing mitochondrial metabolic pathways in the injured kidneys. However, the precise contribution of miRNA:mRNA interactions to chronic disease progression remains unclear.

Given the intricate nature of kidneys, which consist of more than 20 cell types with complex anatomical tubular architecture, this proposal aims to clarify the distribution of miRNA-controlled mRNAs at the tubular resolution. To achieve this goal, we will leverage a spatial transcriptomic approach. To streamline our analysis, we will implement immunofluorescence analysis on injured kidneys, utilizing a combination of protein markers and object identification scripts that automate and definitively identify nephron tubules.

Upon obtaining sets of target mRNA counts along with geometric data from the spatial sequencing dataset, our next step involves determining the specific distribution of target mRNA within nephron tubules. This will be accomplished through our customized data analysis pipeline designed to interpret miRNA:mRNA interactions. The successful completion of this proposal will enable the assessment of miRNA activities within each renal tubule, providing deeper insights into how miRNA-mRNA interactions impact the pathological progression of chronic kidney injury.

Heavy water and hydrogen isotopes such as protium (light hydrogen) and deuterium (heavy hydrogen), have applications in many fields. These include medical, pharmaceutical, optoelectronics and nuclear energy industries. In medical and pharmaceutical fields, heavy hydrogen isotopes are used in isotope related tracing, cancer therapy, nuclear magnetic resonance, and infrared spectroscopy. In energy field, heavy hydrogen isotopes are used as fuels in fusion reactors. Nuclear power fission reactors require extreme efficient cooling. Heavy water can be used as a primary coolant in nuclear engineering.

Unfortunately, the natural abundance of deuterium, is about 0.013 % in surface water. In addition, separating hydrogen isotopes from a mixture is very challenging due to their similar physicochemical properties. Further, conventional separation methods are extremely energy intensive and less effective. Due to these challenges, the US relies on non-allied foreign countries (Russia and India) for heavy water supply. Those supplies are no longer meeting the US demand. Thus, searching for alternative low energy, high efficiency hydrogen isotope separation approaches are of great importance for engineering and medical technologies.

The primary objective of this study is to develop and understand a novel isotope separation technique. We will investigate quantum mechanical transport phenomena of hydrogen isotopes through the two-dimensional monolayer graphene (graphene is a single sheet of carbon atoms arranged in a hexagonal pattern to form the thinnest material).

Student #1 will investigate how one can use quantum tunneling phenomena to separate isotopes through the graphene layer. This quantum mechanical phenomena does not have a classical counterpart (throwing a tennis ball at a brick wall, at quantum mechanical level, the tennis ball has finite probability of penetrating through the wall even its energy is smaller than the potential barrier). Due to the quantum mechanical nature of particles, they can be selectively separated. Isotope binding (sticking) to the graphene layer is possible for some isotopes as their kinetic energy can transfer into the graphene layer, making the vibration of carbon atoms. These vibrations generates “lattice phonons”. The phonon energy spectrum is the central quantity required to calculate isotope-graphene binding. Student #2 will calculate the phonon spectrum for graphene.

Our research aims to explore the role of AGPAT3 in kidney function, particularly focusing on its potential involvement in kidney lipid metabolism and the development of chronic kidney disease. AGPAT3 is one of a group of homologous enzymes responsible for synthesizing lipids important for cell signaling and energy supplies. This enzyme is highly expressed in the kidney. Recently, an rs10084572 polymorphism in AGPAT3 was found to be associated with an increased risk of developing kidney disease in non-Hispanic whites and African Blacks. We also detected growth retardation in Agpat3 knockout (Agpat3-KO) mice. Therefore, in this project, we hypothesize that loss of AGPAT3 alters kidney lipid metabolism, leading to chronic kidney disease and growth retardation.

We plan to achieve the following goals:

1) Assessment of Renal Functions: We will examine whether Agpat3-KO mice demonstrate increased water intake and urine output, altered albumin/creatinine ratio and electrolytes in blood and urine. Changes in these parameters might indicate alterations in kidney function or fluid homeostasis.

2) Evaluation of Kidney Morphology: We will quantitatively assess kidney structure, including the size, shape, and organization of various components within the kidney. Observing kidney tissue from Agpat3-KO mice for any signs of damage or abnormalities could provide valuable information on the impact of AGPAT3 deletion on kidney structure.

3) Analyses of Kidney Lipid Profiles: We will submit kidney samples for mass spectrometry-based lipidomic analyses to analyze lipid species in the kidney. This approach could reveal alterations in lipid profiles associated with AGPAT3 deficiency, shedding light on its involvement in kidney lipid metabolism.

Overall, we aim to uncover a novel role for AGPAT3 in maintaining normal kidney function. Such studies could help our understanding of chronic kidney diseases. Additionally, linking AGPAT3 to kidney lipid metabolism and function might offer novel therapeutic avenues for managing kidney-related disorders.

In the Langridge lab we study how cells communicate via cell surface proteins that are mechanosensitive. Specifically, these receptors receive a pulling force applied along a connection with a signal sending cell. The prototypical example of such communication is the Notch receptor, which has been the subject of intense investigation in my lab. We now have evidence that other important receptors might be activated in a similar way, which has opened-up exciting new avenues of investigation into mechanical force in cell communication. Specifically, we will determine whether the cell surface receptor Dscam is mechanosensitive as it acts to guide neurons to form synaptic connections in the brain. Our approach uses cutting edge Drosophila genetics combined with molecular biology techniques and microscopy.

Down syndrome cell adhesion molecule (Dscam) is an important receptor in the development of Drosophila and human brains alike. Its mysregulation is involved in Down Syndrome and other developmental disorders. Dscam controls the adhesion or repulsion between neurons, a process that is vital in establishing the correct wiring of the brain. As the nervous system develops, a neuron must make synaptic connections with a few other neurons within a mass of many thousands of neurons. To achieve this remarkable feat, neurons literally crawl toward their target neurons and touch them, via the cell surface protein Dscam, which identifies whether the target is correct, in which case the neuron adheres strongly to its partner, or whether the target is incorrect, which leads to the neuron moving away and avoiding the other cell. Our hypothesis is that this Dscam-mediated neuronal avoidance requires proteolytic cleavage or cutting of Dscam and that this cleavage is triggered in response to force. Such a mechanism is very similar to the activation of Notch in the fly wing.

Our lab is poised to apply the extensive expertise we have developed to investigate Notch in the wing to a whole new area: the activity of Dscam in the brain. Simmie has previously investigated Notch using these techniques and is now excited to have the opportunity to develop new skills relevant to Dscam and brain development.

Research indicates that music has value beyond conventional uses in entertainment or ceremonial contexts. For instance, the NIH partners with the JFK Center for Performing Arts to operate “Sound Health” (https://www.nih.gov/research-training/medical-research-initiatives/sound-health). Aims of Sound Health include expanding research on how music interacts with brain circuitry and behavior. Thus, basic and mechanistic research on the intersection of music and psychology are of interest.

Research examining the interaction of musical variables such as tonality and meter to influence individuals’ perception of music may have translational value. Tonality refers to the hierarchical arrangement of pitches (musical notes) in a musical key. For instance, some notes sound “good” with other notes, whereas as other don’t seem to fit as well. Meter refers to alternations of emphasis in time (i.e. where the beat is). Research on tonality and meter indicates that each have hierarchies (e.g. some notes in a key occur more than others; strong beats tend to occur in certain places), and interact to impact individuals’ perceptions of music. Research on perception of music primarily relies on self-report methods (e.g. rating the “goodness” of music). Another method for assessing perception is the analysis of behavior (e.g. actually “choosing” to listen to one melody over another). Interestingly, evidence across many psychological domains indicates weak correlations between self-report and behavioral measures of the same construct (i.e. there is a difference between what one says and does).

The objective of the current proposal is the development of behavior-analytic methods for the assessment of tonality, meter and music preference. Specifically, the research team will develop a means of assessing how tonality and meter interact to influence participants’ choice behavior. The project will test the hypothesis that music in which tonal and metric hierarchies are aligned will be preferred over music in which these hierarchies are misaligned, and determine if behavior analysis is consistent with self-report. Participating students will learn about (western) music theory and the experimental analysis of behavior, engage in experimental design, programming using JavaScript, and draft an IRB proposal. Students will have a variety of opportunities for growth, and contribute to a new interdisciplinary research project.

The Office of the Provost, under the leadership of Dr. Neil MacKinnon, is engaged in health policy research on a multitude of topics. The student will be engaged primarily in two of these projects, exposing them to national and international public health issues. The projects are described below.

1. National Analysis of Health Professionals' Workplace Mental Health and Wellbeing

Mental health and well-being are rising concerns in the United States workforce. These concerns are more pronounced among healthcare workers. Left unaddressed, burnout is likely to negatively impact many facets of healthcare. In October 2022, the U.S. Surgeon General released the “Framework for Workplace Mental Health and Well-Being” in response to increasing concerns. The framework includes five “Essentials” centered around Worker Voice and Equity. These Essentials include “Protection from Harm”, “Connection and Community”, “Work-Life Harmony”, “Mattering at Work”, and “Opportunity for Growth”. Our team transformed each item from the framework into a workplace mental health and well-being survey (The Augusta Scale). We piloted the Augusta Scale with Georgia AHEC preceptors and conducted analyses to examine healthcare professionals’ well-being, as well as determine the psychometric soundness of the scale. We have now partnered with the National AHEC Organization to distribute the survey to preceptors nationally.

1. Analysis of Commonwealth Fund Data Related to Hospital Discharge Communication Problems.

The transition from hospital care to another point of care is a critical moment in ensuring positive patient outcomes and safety. Communication and collaboration during this process are vital to ensure the patient receives the appropriate supplemental information about their care, particularly regarding medications or new providers they will see following discharge. Efforts towards improving discharge communication have been associated with lower rates of rehospitalization, higher rates of 30-day treatment adherence, better patient satisfaction, and, to some extent, improved knowledge of medication and diagnosis. For this project, we aim to examine which nations have the highest rates of “poor discharge communication” (PDC) among adults and factors associated with a greater likelihood of PDC, allowing for targeted programs to address shortcomings.

Attending summer programing is associated with improvements in children’s academic performance, positive social-emotional development, and improved mental and physical health. These positive outcomes are more pronounced for children from households with low income who, under typical circumstances, may be unable to access summer programs due to barriers like cost and transportation. Studies providing vouchers (i.e., scholarships) and transportation to summer programing have improved attendance for children from low-income households and have led to improved health and academic outcomes. That said, efforts to replicate these findings on a larger scale (i.e., providing a larger number of scholarships and transportation at the county, state, or national level) are likely to face significant obstacles due to constraints within individual summer programs such as space, staffing, funding, and organizational or political support. These potential barriers to large-scale implementation may be mitigated with thoughtful planning that utilizes existing knowledge about increasing programming capacity. We propose a qualitative study conducting one-on-one interviews with senior staff of summer programs in Georgia and South Carolina to understand ways their existing programs have previously navigated changes to their programing and capacity. This study could provide contextual information relevant to effective, larger scale implementation of accessible summer programing to improve the health and wellbeing of children.

Objectives

1.To conduct qualitative focus groups and interviews with senior staff at summer program for K-12 children across Georgia and South Carolina.

2.Characterize the experiences and perceptions of senior staff at summer program for K-12 children across Georgia and South Carolina during periods of program change (via guided retrospective reflection).

3.Identify strategies and adaptions (useful and otherwise) used by senior staff at summer program for K-12 children across Georgia and South Carolina during periods of change.

Last year, we submitted the results of our project as a proposal to the National Institutes of Health (NIH). We received feedback and suggestions from NIH grant review comments, which we addressed in this year's proposal. This year's proposal aims to develop new generations of drug candidates for breast cancer. We hope that the outcomes of this year's proposal will help us create a robust NIH RO1 grant proposal.

Natural products (NPs), chemical compounds produced by microorganisms and plants, are a very important source of drugs and drug leads. The clinical use of NPs was greatly intensified by the discovery and isolation of the first pure antibiotic penicillin in 1928. Since then, many NPs have been isolated and saved billions of people. In the past 40 years, more than 60% of U.S. Food and Drug Administration-approved small molecule drugs are NP-related. However, infections by antibiotic-resistant pathogens are increasing globally and are anticipated as one of the greatest threats to human health in the future. Therefore, new drug candidates for use in clinics are in high demand.

The discovery and development of a new drug from scratch require 10s-100s of millions of dollars and normally more than 10 years. Since a minor change in the chemical structure of compounds may dramatically alter their biological activities, modification of known molecules is a promising cost- and time-effective approach to developing new drugs. However, it is significantly challenging to modify a specific part of the structure in a specific way by conventional organic chemistry, especially when the chemical structure of the parent compound is complex, as is the case with NPs. Therefore, using the biological catalysts “enzymes” as TOOLs for the modification of bioactive compounds has gathered much attention in the drug discovery field.

The small change catalyzed by enzymes, which we are interested in, is homologation. Homologation is a chemical transformation that inserts a methylene group (-CH2-) into the amino acid side chain. Homologation is catalyzed by four enzymes sequentially. The first novel enzyme of those called HphA has been characterized in our lab. To use the enzyme as a tool, it is important to show the amenability of the enzyme to engineering. This project will focus on mutating HphA to mimic the activity of its homologous enzyme called LeuA. This work will shed light on the development of a new enzymatic tool to modify highly complex peptide NPs, which are more biologically stable due to the resistance to the peptide degrading enzymes, such as peptidases.

The consideration of random hypothesis in studying some influencing factors affecting the growth or decline of a tumor is crucial. By analyzing the effects of stress on the volume of tumor growth in a random environment, we develop stochastic models describing the dynamics of the tumor growth based on random adjustments to the population’s intrinsic growth rate, carrying capacity, and tumor treatments. Apart from the models’ ability to capture fluctuations, the availability of a shape parameter in the models gives it the flexibility to describe a variety of population/tumor data with different shapes. The distribution of the stressed population size with or without treatments is derived and used to calculate the minimum amount of chemotherapy needed to cause shrinkage or eradication of a tumor. The work done is applied to analyze tumor growth using published data comprising of the volume of breast tumor obtained by orthotopically implanting LM2-4LUC+ cells into the right inguinal mammary fat pads of 6-to 8-week-old female Severe Combined Immuno-Deficient mice.

The long-term goal of my laboratory is to better understand movement disorders such as dystonia, dyskinesia, essential tremor, and Parkinsonism. Movement disorders are neurological conditions that affect at least 1% of people over age 60 worldwide and are characterized by slowed movements, loss of voluntary muscle control, or rigid posture. Clinical management of these lifelong conditions is unfortunately very limited, which has resulted in an economic burden climbing at an exponential rate that exceed $50 billion in 2020.

After decades of unclear etiology for movement disorders, we now know of numerous genetic markers and brain regions essential for disease progression. Multiple variants in KCTD17, the gene that encodes the protein Potassium Channel Tetramerization Domain 17 (KCTD17), have been identified in patients with a particular form of movement disorder called dystonia. Pioneering work from my laboratory and others has provided clues for how KCTD17 may contribute toward dystonia. First, KCTD17 is highly enriched in a part of the brain, called the striatum, that is critical for movement. Second, KCTD17 modulates a specific node of neurotransmission: signaling through an adenosine receptor that is selectively expressed in striatal neurons.

Therefore it is conceivable that adenosine-based therapeutics may provide efficacy in dystonia patient’s lacking proper KCTD17 function (i.e. harboring KCTD17 loss of function mutation). To first test our hypothesis in a pre-clinical model, we generated a novel KCTD17 striatal-specific knockout mouse (KCTD17 KO). Excitingly, conventional rodent behavioral assays identify that KCTD17 KO exhibit aspects of dystonia, which are partially rescued by prolonged pharmacological blockade of the striatal adenosine receptor. Although powerful, conventional rodent behavioral assays have numerous shortcomings. The dystonia test for instance measures the angle and duration of rodent hindlimb extension when held by the tail for 10 seconds. Such an approach provides a binary readout aimed at generating rudimentary statistics that do not reflect naturalistic behaviors. Moreover the narrow dynamic range of data obscures drug-specific behavioral effects, side effects, and distinguishing action of drugs belonging to the same pharmacological class.

Here, we will utilize a recently reported mouse behavioral tracking system referred to as Motion Sequencing (MoSeq) to examine how different adenosine-based therapeutics shape dystonic phenotypes in KCTD17 KO. MoSeq overcomes traditional behavior limitations by recording mice for multiple hours followed by unbiased machine-learning algorithms to quantify dozens of behavioral motifs (head turns, standing, grooming, walking, resting, running, climbing, etc). Additional advantages of MoSeq include utilization of inexpensive cameras (e.g. old smartphone), free open-source software, and non-invasive data acquisition (i.e. mouse explores a familiar arena). This results in a large scale dataset that identifies specific motor patterns influenced by pharmacological treatment. Therefore we will learn meaningful effects of dystonic therapeutics on all aspects of rodent muscle coordination, rather than information from classical behavioral assays.

We will utilize 4 cohorts of KCTD17 KO mice (8 animals per group/32 total), which are currently viable in our laboratory. We will test three distinct antagonists for the striatal adenosine receptor: caffeine (natural compound), theophylline (acute bioavailability), istradefylline (extended bioavailability), and vehicle control. Animals will be injected (I.P.) and monitored for three hours per day. Our IACUC protocol (#2020-1036) was approved on 12/21/2023 and is valid until 12/21/2026. We are hopeful the results will be a critical first step toward examining therapeutic options for dystonic patients with KCTD17 variants while also a launchpad for the SSP student’s career in science by opportunity to spearhead an innovative

The extracellular matrix (ECM) plays an instrumental role in the support system of any vessel. It is a structure made of proteins (collagen, elastin, glycans) that surrounds the muscle tissue of the vessel. Known functions of the ECM include cell signaling, support, and attachment. The primary type of tissue being investigated is the aorta, a long tubular vessel extending from the heart to the body's abdominal area. It distributes blood from the heart to the rest of the body. This project will investigate the protein integrity of the aorta in the Four Core Genotype (FCG) mice model. The proteins found in the ECM contribute to the tensile strength and elasticity of the ECM. However, the function of these proteins can be interfered with due to variables that may alter the protein integrity of the ECM and further cell activity. These variables include vascular aging (arterial stiffness), enzyme activity, and hypertension. Therefore, this project aims to understand how the protein integrity of the aortic extracellular matrix is affected and how it varies in FCG mice based on sex differences. These sex differences can be hormonal (estrogen and testosterone) and chromosomal between male and female mice. The FCG mouse models used in this investigation involve male (M) and female (F) with either XX or XY genotypes. To analyze the protein integrity of the ECM in the aorta, Anne will use the 560-TP (tissue puller) equipment, which is a force-induced machinery to measure the stress-strain and force-displacement relationship of the aorta using the Myo-Pull software. The TP will observe the tensile strength of the ECM and will use a control aorta (with no enzyme treatment), an aorta treated with elastase, and an aorta treated with collagenase. Other methods used include imaging of the ECM such as MTA (Masson Trichome Analysis), data analysis software, western blotting, and microarray to identify protein composition and sexual differences.