Ball State University

NSF Awards · FY 2026 · 2026-07

Classical calculus concerns itself with smooth functions, curves, and surfaces inside our standard Euclidean geometry. Nowadays, many problems in pure and applied mathematics benefit from extending calculus tools beyond these smooth, Euclidean contexts. This includes the study of non-smooth functions and sets, abstract geometries different from our own, and fractal spaces with interesting behavior at many scales. The project aims to understand these objects in a number of ways: by studying the ways curves can pass through them, by decomposing them into simpler pieces, by embedding or folding them into classical geometries, or by approximating them with linear objects – measuring how “flat” they are at various locations and scales. Non-smooth analysis and geometry are important in many areas of pure and applied mathematics and computer science, since non-smooth problems arise in studying large data sets, in computational questions, and as limiting cases of smooth problems. The project also emphasizes techniques and results that are "quantitative": providing guaranteed estimates independent of the particular function or geometry being studied. The project's broader impacts include organizational work in the analysis community, focusing on early-career researchers, and impact on the research environment in the PI's home department through invited speakers and improved advising and mentoring. In general, the project contributes to a more robust understanding of complex and high-dimensional mathematical objects that appear in many problems. More specifically, the PI is continuing his study of newly constructed “coarse” and “pointwise” tangent fields for non-smooth sets in high-dimensional ambient spaces, analogous in some ways to the tangent planes of a smooth surface. These provide new ways to describe the structure of non-smooth sets. Properties and applications of this construction are related to questions, also under investigation in the project, about when one can project, embed, or fold high-dimensional sets into a lower-dimensional space without too much distortion of the geometry. Flatness properties of sets and mappings also arise in connection with parametrization problems for manifolds (when is a topological sphere bi-Lipschitz or quasisymmetric to a standard sphere?) and decomposition problems for mappings (when can we break a complex geometric mapping into a sequence of steps with small distortion, or break its domain into sets on which it acts more simply?). Related approximation, parametrization, and embedding questions also apply even for abstract metric spaces, which are also within the scope of the project. The PI studies these questions with a mixture of techniques from geometric measure theory, analysis on metric spaces, quasiconformal geometry, and geometric topology. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2026 · 2026-05

Many chemicals, fragrances, and drugs have molecular structures that include aromatic groups. Synthesizing these molecules is complicated and involves multiple steps, which often leads to low yields. Each step involves blocking all reactive sites on the molecule except the one targeted for a chemical reaction. Once that reaction is complete, the blocked sites must be unblocked to prepare for the next reaction. Each repetition of this cycle reduces the overall efficiency of the process. Each step also adds to the energy requirements and solvent waste generated. Using enzymes to drive reactions may reduce energy and solvent waste. This project will investigate modifying certain selected enzymes so that they can react more efficiently with molecules that contain aromatic groups. Experiments will be performed by teams of undergraduate researchers. The project will provide students with valuable experimental and analytical skills and contribute to the future U.S. biomanufacturing workforce. Previous research on enzyme catalysis has demonstrated a benefit deriving from remodeling the substrate tunnel. This strategy will be applied to three families of aromatic-metabolizing enzymes: 1) extradiol dioxygenases, 2) aromatic peroxygenases, and 3) ferulic acid decarboxylases. Variants of each of these enzyme families that have expanded reactivity for aromatic compounds will be developed using directed evolution platforms. Enzyme engineering studies will follow a “design-test-build-learn” cycle. Large variant libraries will be produced using rational engineering and will be screened for enhanced activity. AI-based protein modeling techniques will identify substitutions that might stabilize interactions between the enzyme and substrate. For each round of selection, 6-10 residues lining the substrate tunnel will be selected for mutagenesis, and variant libraries will be built through substitution of each selected residue with residues capable of establishing π-π stacking interactions with aromatic substrates (phenylalanine, tryptophan, tyrosine, histidine) and with methionine. Potential contributions of this research include A) new, sustainable catalysts with valuable applications in organic synthesis and bioremediation; and B) the demonstration of the broad practical utility of tunnel modification enzyme engineering methods. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2026 · 2026-01

This project will provide a scientific roadmap for saving threatened species from extinction. As animal populations shrink and become isolated, they lose the genetic diversity that is essential for their long-term survival. A powerful conservation tool called "genetic rescue" can restore this diversity by mixing individuals between isolated populations. However, this action carries a risk: if the parent populations are too genetically different, their offspring may be less healthy or less able to survive, a problem known as "outbreeding depression." Because of this, conservation managers and organizations have been hesitant to use this strategy. This project will study the risk of outbreeding depression in the threatened Chiricahua Leopard Frog in Arizona and New Mexico. By carefully breeding frogs from populations with different levels of genetic relatedness, the researchers will identify the optimal genetic distance that boosts population health without negative effects. The project will also test if these genetic crosses produce frogs that are more resistant to a deadly fungal disease that threatens amphibians globally. The results will give wildlife managers the genetic rescue data they need to recover this frog species and will create a pathway for saving other endangered species using this method. This project also provides hands-on research training for university and high school students and will share the story of amphibian conservation with the public through a professional documentary film. This research will conduct a comprehensive, experimental assessment of outbreeding depression in a federally threatened species, the Chiricahua leopard frog (Lithobates chiricahuensis; CLF). Using a recent, rangewide genomic analysis that identified four primary genetic clusters and finer-scale subdivisions, the researchers will implement a multi-year, controlled breeding program at two field stations in Arizona and New Mexico. The experimental design involves a series of hierarchical crosses between CLF populations of decreasing relatedness, from within-population controls to maximally divergent inter-cluster pairings. Researchers will measure key fitness proxies in the resulting offspring, including egg hatching success, survival to metamorphosis, larval growth rate, and size at metamorphosis, to establish any threshold at which outbreeding depression occurs. To assess the applicability of these outcomes in a natural context, juveniles from successful crosses will be introduced into monitored wild populations. The project team will use capture-mark-recapture (CMR) methods for demographic monitoring and genome-wide polymorphisms for genomic surveillance, tracking changes in allele frequencies and population size over time. Finally, the project will evaluate if genetic mixing impacts disease resistance by conducting standardized laboratory inoculation experiments with the lethal amphibian pathogen Batrachochytrium dendrobatidis (Bd) on offspring from select crosses. This multi-faceted approach, integrating controlled experiments with in-situ monitoring and disease challenges, will directly inform adaptive management strategies for the CLF and provide a transferable framework for applying genetic rescue in other species of conservation concern. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-10

Animal cells are partially defined by the relationship between their two different sources of DNA, one from the nucleus and one from the mitochondria. Efficient communication between these sources of DNA is essential for energy production and survival, and their compatibility can influence how species reproduce, regulate their physiology, and diverge from one another. Because the ongoing collaboration between the nucleus and mitochondria is foundational to survival, opportunities to study the consequences of miscommunication between these cellular components are rare. This project uses a unique group of all-female salamanders that possess an evolutionary distinct mitochondrial genome that is forced to interact with nuclear genomes taken from males of other species. How these salamanders have persevered for millions of years while managing their enormously complex genomic challenge can help us understand how other organisms suffer severe consequences when their mitochondrial and nuclear genomes produce conflicts. This project will integrate across biological disciplines from different universities and students will acquire training for careers in diverse, data-driven fields. At the same time, the data from this project will be directly integrated into university curriculum to forward initiatives that increase students’ data analytics and scientific communication skills. Understanding how mitonuclear interactions evolve and are maintained is necessary for understanding the consequences of mitonuclear mismatch, whether due to new mutations or interbreeding between species and populations. To connect mitonuclear genotypes to functional phenotypes, this research includes measurements of sequence evolution, mitochondrial performance, and whole-animal metabolism. This will provide a comprehensive picture for how mitonuclear relationships in all-female salamanders have evolved and are maintained over millions of years in the face of frequent introgression. The first project aim will describe the evolutionary relationships between the mitochondrial and nuclear genomes being shared between salamander groups over generations and millions of years. The second aim will estimate measures of selection for genes originating from the mitochondrial and nuclear genomes that must interact to form basic metabolic pathways. The third aim will connect the molecular measurements to physiological performance at both organelle and whole-animal scales. The final aim will provide new whole-genome resources for salamanders to understand the genomic context of identified mitonuclear interactions. Despite their importance in biomedical, evolutionary, and ecological studies, salamanders have been an undersampled taxonomic group for genomic resources due to the technological challenges issued by large, repetitive genomes. This project will provide much needed genomic resources for salamanders broadly. This project is jointly funded by the following programs in the Directorate for Biological Sciences: Evolutionary Processes in the Division of Environmental Biology, Genetic Mechanisms in the Division of Molecular and Cellular Biosciences, and Physiological and Structural Systems in the Division of Integrative Organismal Systems. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-09

Many organic compounds that contain chlorine can remain in the environment for a long time, potentially harming human health and ecosystems. Chlorinated organic solvents, such as trichloroethylene (TCE) and perchloroethylene (PCE), are common groundwater pollutants in the U.S. and worldwide. Many people have been exposed to TCE and PCE through contaminated drinking water, raising health concerns. Decomposing these contaminants is challenging because of the strong carbon-chlorine bond. This project aims to develop new catalysts based on bismuth oxide to break down these pollutants. The research will design earth-abundant, eco-friendly nanocomposites made of two metal oxides arranged in particular ways to degrade organochlorine compounds using sunlight. Adding a small amount of environmentally friendly carbon material will enhance the catalyst's activity. This project will engage students in research activities to enrich their education by exploring new knowledge, developing key skills, and inspiring students to pursue careers in STEM. The goal of this project is to develop visible light-activated photocatalysts based on heterostructured bismuth-based metal oxide nanomaterials for the sustainable degradation of persistent chlorinated organic contaminants. The hypothesis is that designing Aurivillius/pyrochlore Z-scheme heterojunctions of bismuth-based metal oxides will enhance the redox potential of the photocatalyst band gap, enabling the degradation of chlorinated organic pollutants under visible light. To achieve this, the project will develop bismuth vanadate/Bi2M2O7 catalysts with engineered Z-scheme heterojunctions to boost visible-light-driven catalytic activity. Incorporating carbon dots (CDs) as sustainable, alternative cocatalysts to noble metals on the surface of bismuth-based metal oxides will improve light absorption and charge transfer. The properties of bismuth-based Z-scheme heterojunction nanocomposites will be investigated using techniques such as electron microscopy, X-ray diffraction, electrochemistry, and UV-vis spectroscopy, providing fundamental insights into designing more effective catalysts. The photocatalytic activity of these materials will be evaluated in degrading chlorinated pollutants like trichloroethylene and perchloroethylene, with performance compared to established materials such as TiO2. The project will explore the relationship between material structure, band gap alignment, and the mechanisms of visible-light-driven degradation, aiming to optimize reaction conditions for high efficiency and minimal toxic byproducts. Ultimately, this work advances the development of visible-light-responsive Z-scheme photocatalysts, providing the science and engineering fields with a scalable platform for creating sustainable technologies that utilize solar energy to remove persistent environmental pollutants. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NSF Awards · FY 2025 · 2025-01

Daylight and window views provide comfort, health and well-being. However, children with Autism Spectrum Disorder (ASD) are often hypersensitive to environmental stimulation, which leads some schools for ASD children to keep windows covered to block natural light and avoid potential distractions. Guidelines for lighting in these schools could help improve the sensory behaviors and health of children with autism. This project will (i) discover evidence linking daylight and behavioral responses in autism educational settings, and (ii) develop and implement guidelines for inclusive indoor environments while harnessing the benefits of natural light for the children. The broader impacts of this project are: (i) to integrate knowledge from different disciplines, train cross-disciplinary students and provide a breakthrough in understanding the impact of daylight on behavioral response of ASD children; (ii) to implement findings in autism educational facilities in collaboration with local teachers and stakeholders; (iii) to create educational materials that motivate teachers, parents and caregivers to establish preventative protocols for outbursts and encourage healthy behaviors for ASD children with respect to daylight; and (iv) raise awareness in the autism community for using natural light to improve the quality of life for children with autism. The project will transform the visual environment design and operation in educational environments for children with ASD. Through a pioneer framework of experimental methods, computational predictive models and evidence-based reverse engineering operation, this research will establish a new paradigm and build the foundation for a universal platform to optimally design and control daylight for this sensitive population. First, a focused experimental study will be conducted with 50 children with ASD in well-designed educational settings under real daylighting conditions. A flexible sensing network will be deployed to monitor and process pixel-wise information of dynamic luminance distributions. At the same time, seven behavioral aspects and sensory profiles will be assessed along with the children’s task performance capabilities. The data will be used in probabilistic and machine-learning-based models, to predict and classify dynamic behavioral responses to daylight-induced stimulation conditions. In turn, a generalized daylight simulation approach coupled with reverse engineering operation and optimization will translate these findings into comprehensive daylighting design and operational guidelines implemented in real autism schools in collaboration with teachers, parents and autism community stakeholders. These engineering designs are expected to refine daylighting best practices for ASD children to improve sensory behavior, minimize outbursts, and provide better everyday life for this population. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

NIH Research Projects · FY 2024 · 2024-09

PROJECT SUMMARY MitoNEET is a druggable target, with recognized roles in type-2 diabetes, cancer, and Parkinson’s Disease. The redox- active [2Fe-2S] cluster of mitoNEET, localized in the cytosol at the outer mitochondrial membrane, has enzymatic capacity to convert thiol-containing molecules known to regulate the cellular redox balance, such as cysteine and glutathione. The electronic properties and stability of the [2Fe-2S] cluster of mitoNEET are sensitive to pH, mutagenesis, ligand binding, and covalent modification. Cluster instability and release from mitoNEET cause an increase of free iron in the cytosol. The iron increase is a known harmful event that at the least causes oxidative stress and at most kills the cell through the initiation of ferroptosis. Metabolic activity towards thiols combined with the instability of the cluster makes mitoNEET well- positioned to act as both a sensor for free thiol content in cells and a putative perpetrator of ferroptosis. We hypothesize that mitoNEET has a unique role in contributing to redox homeostasis through the metabolism of sulfur-containing intermediates and signaling into the ferroptosis pathway. It contributes to the cell's ability to maintain physiological glutathione concentrations and the cytosolic free iron pool.

NIH Research Projects · FY 2025 · 2021-09

ABSTRACT Therapeutic monoclonal antibodies (mAbs) represent a rapidly expanding class of therapeutic agents, offering promise for treating various cancers, including prostate cancer (PC). However, their complex structure, elevated production cost, cross-reactivity, immunogenicity, and instability have limited their utilization in modern medicine and have prompted exploration for alternatives. Accordingly, nucleic acid aptamers, known for their high affinity and specificity (functions that mimic mAbs), have recently emerged as compelling substitutes in diagnostic, therapeutic, and targeting applications. By leveraging the advantages of aptamer technology and utilizing recently developed modular, enzymatically stable, and non-immunogenic chemically modified triangular nucleic acid nanoscaffold, a panel of highly stable next-gen NANPs capable of harboring numerous PC-binding aptamers in controlled manner will be constructed. This design will mirror the structural diversity of mAbs, including monomers (IgD, IgE, IgG), dimers (IgA), and pentamers (IgM). The enzymatically stable 2’F-modified RNA aptamer, recognized for its robust binding affinity to Prostate Specific Membrane Antigen (PSMA) on PC cells, stands as the primary aptamer candidate. In contrast to monoclonal mAbs, the resulting set of NANP-mAbs bypass the need for animal use in production. Also, compared to mAbs which require storage at -80 °C, the NANP-mAbs can be stored at room temperature for prolonged periods of time when dehydrated. Utilizing programmable NANPs synthesized and assembled in vitro ensures remarkable batch-to-batch consistency. Collectively these factors enable economical, highly accurate, and large-scale production of NANP-mAbs for both PC detection and treatment purposes. The long-term objective of this NIH AREA R15 proposal to develop next generation NANP-mAbs platform applicable to therapeutic interventions across various diseases and particular PC. The three Aims of this proposal are: 1. To construct and characterize next-gen NANP-mAbs assembled from stable and compact triangular nanoscaffolds; 2: To evaluate stability of the proposed NANP-mAbs in blood serum and study binding affinity to PSMA; and 3: To assess binding specificity of these NANPs-mAb to PC cells. The short term goal is to create a repertoire of nucleic acid-based nanoparticles capable of hosting multiple human PSMA binding aptamers along with an imaging dye, enabling synergistic and amplified PC-specific binding outcomes to be achieved. Binding affinities and cellular internalization of proposed set of next-gen NANP-mAbs will be rigorously compared and then screened for suitability in subsequent studies using in vivo models. Ultimately, the insights gathered from this innovative project will drive the development of robust Nucleic Acid Nanotechnology platforms with broad biomedical applications, aligning well with the mission of the National Institute of Biomedical Imaging and Bioengineering to "transform through technology development, our understanding of disease and its prevention, detection, diagnosis, and treatment."

NIH Research Projects · FY 2024 · 2020-05

This proposal uses innovative approaches to uncover underlying molecular mechanisms and develop a novel treatment strategy for frontal temporal dementia (FTD), the second most common form of young-onset dementia and an Alzheimer-disease related dementia. Unfortunately, there are no treatment options that prevent or slow FTD. A mutation in C9ORF72 (C9) is the most common cause of FTD and amyotrophic lateral sclerosis (ALS), collectively referred to as C9 ALS/FTD. This mutation leads to an abnormal excess of DNA and RNA structures, termed G-quadruplexes. Increased G-quadruplex burden contributes to accumulation of toxic RNAs and proteins leading to neuron degeneration and disease onset. As such, C9 ALS/FTD is fundamentally a ‘G-quadruplex disease’. Within the cell reside helicase enzymes that unwind G-quadruplexes. DHX36 is a major G-quadruplex helicase, accounting for the majority of G-quadruplex helicase activity in human cells. In the previous funding period, it was shown that DHX36 enhances production of toxic C9 proteins via repeat-associated non-AUG (RAN) translation. It was also shown that RAN translation of toxic C9 proteins during cellular stress requires DHX36, linking DHX36, stress, and RAN translation for the first time. DHX36 localizes to stress granules following stress, however it is unknown if the presence of DHX36 in stress granules is directly connected to DHX36 effects on C9 RAN translation. For Aim 1, it is hypothesized that loss of DHX36 reduces C9 protein translation through reduction of stress granule abundance. This hypothesis will be tested using C9 patient- derived cells, mouse primary brain neurons, and in vivo transgenic mouse models. In addition to a cytoplasmic effect of DHX36 on RAN translation, preliminary data suggest that DHX36 may protect C9 ALS/FTD cells from increased DNA damage in the nucleus. These observations suggest that nuclear DHX36 may be protective while cytoplasmic DHX36 may exacerbate C9 ALS/FTD. For Aim 2, it is hypothesized that specifically targeting cytoplasmic DHX36 is a viable therapeutic strategy that reduces toxic C9 protein production while preserving protective effects of nuclear DHX36. This hypothesis will be tested using human C9 ALS/FTD patient-derived neuronal progenitor cells. This research builds on a long-standing collaboration between three research groups led by Dr. Philip Smaldino (Ball State U.), Dr. Yuh-Hwa Wang (U. of Virginia), and Dr. Peter Todd (U. of Michigan), with additional support from Dr. Lindsey Hayes (Johns Hopkins U.) and Dr. Ashley Kalinski (Ball State U.). The proposed studies will be the first to determine the role of DHX36 in stress responses and genomic integrity in C9 ALS/FTD and is poised to identify DHX36 as a novel therapeutic target. Undergraduate and graduate students will be integrated at every stage of the project allowing them to gain authentic experience with innovative cell and mouse technologies applied to a deadly human disease. Completion of this work will include the training of ~24 research lab students and over 150 students in Course Undergraduate Research Experiences (CURE) taught by the PI, giving this proposal high potential to inspire future dementia-disease researchers.

NIH Research Projects · FY 2025 · 2017-02

Project Summary The human fungal pathogens C. albicans and C. auris are members of the CTG fungal clade which diverged roughly 200 million years ago from the Saccharomyces lineage. Work from previous funding periods suggests pseudouridylation and pseudouridine degradation are not conserved between CTG and Saccharomyces lineages. The Bernstein Lab will continue to characterize these processes in C. albicans and expand investigations to C. auris, an important emerging fungal pathogen with isolates that are resistant to all known antifungal therapeutics. This work will reveal fundamental differences in RNA modification processes between fungal lineages. Furthermore, the processes of pseudouridylation and pseudouridine degradation are not conserved in mammals, but some appear to be conserved in additional fungal pathogens. Pus1 is a pseudouridine synthase predicted to modify a variety of RNA substrates. In Aim 1, experiments will explore how heavy metals affect C. albicans Pus1 localization, determine if Pus1 A and B alleles interact with distinct cohorts of proteins, identify Candida nuclear targeting sequences, and identify Pus1 substrates. This work will be carried out by undergraduate and master’s students and will answer long standing questions regarding allele heterogeneity and stress response in C. albicans. Pug1 degrades pseudouridine. Aim 2 experiments will determine if abrogation of pseudouridine degradation affects C. auris growth, biofilm formation, or antifungal tolerance; identify Pug1 interactors; and determine if PUG1 deletion leads to a defect in virulence using a wax moth and planaria model system. This will be the first characterization of pseudouridine degradation in C. auris and one of the first characterizations of RNA metabolism in C. auris. Undergraduate and master’s students will be involved in all aspects of the proposed experiments providing excellent training opportunities for a diverse team of students. In addition to these two Aims, two of the classes designed and taught by the PI each year will be leveraged to provide the undergraduate and master’s students taking those classes an opportunity to examine important appropriate aspects of molecular and fungal biology. As part of their in-class laboratory activities, between 25 and 50 undergraduates a year will participate in focused research projects, working on important research questions using innovative approaches under direct supervision of the PI. The 2022 NIAID strategic plan states one of the Institute’s priorities is to “support basic and clinical research to better understand, diagnose, treat, and prevent infectious diseases and immune-mediated disorders—many of which have far-reaching global consequences—including fungal diseases.” Consistent with this vision, our research investigates RNA modifications in two important human fungal pathogens, C. albicans and C. auris. Our work seeks to better understand how these pathogens differ from humans at the molecular level. As such, this research has the potential to identify novel antifungal targets.

NIH Research Projects · FY 2024 · 2016-12

PROJECT SUMMARY The Molecular Transducers of Physical Activity Consortium (MoTrPAC) is designed to discover and characterize the range of molecular transducers that underlie the effects of exercise in humans. MoTrPAC was launched in 2016 with six adult clinical centers and a pediatric center that have collaborated to generate extensive Manual of Operations to guide research protocols involving all aspects of the clinical operations (Phase I). Phase II began in the fall of 2019 with all human clinical centers showing excellent progress towards initial recruitment goals and implementation of the protocol. The initial goal set forth by NIH was to recruit 270 children (10-17 years of age) and 1980 sedentary adults (age 18 years or greater) that are randomized to endurance training (170 youth, 840 adults), resistance training (840 adults), or non-exercise controls (50 youth, 300 adults). An additional group of highly active endurance (50 youth, 150 adults) and resistance (150 adults) trained individuals serve as comparators and are not participating in the MoTrPAC exercise training programs. The recruitment and enrollment approach are sex balanced and with participants across a wide range of ages (10-17, 18-39, 40-59 and >60-year age groups) and of different races. Due to the COVID-19 pandemic, MoTrPAC activities were suspended for over a year (beginning in March 2020) with continued constraints through 2022. Despite the numerous challenges encountered as a result of the pandemic, recruitment activities at the adult and pediatric clinical centers have accelerated to a rate that is projected to successfully achieve the target enrollment numbers by the end of the new award period. This led to the NIH Common Fund to release the current NOFO (RFA-RM- 23-010) to provide MoTrPAC with funding to complete recruitment and follow-up for the clinical studies, including finishing mechanistic randomized controlled trials of sedentary adults and children and observational studies of highly active adults and children. This will enrich the participant cohorts that are critical to understand exercise adaptations and heterogeneity across age, gender, and minority groups. Altogether, this extension will allow MoTrPAC to complete the intended goals as originally envisioned and will provide a more complete public database of the health benefits of exercise and provide insight into how physical activity mitigates disease.

NIH Research Projects · FY 2026 · 2014-09

PROJECT SUMMARY Protein quality control (PQC) systems maintain cellular health by targeting damaged or misfolded proteins for degradation. In the endoplasmic reticulum (ER), where folding of secretory and membrane proteins imposes a major PQC burden, ER-associated degradation (ERAD) clears misfolded or mislocalized substrates. Emerging evidence suggests that cytoskeletal components are essential for normal ERAD function. This project investigates the role of the conserved microtubule-associated kinesin-14 motor Kar3-Vik1 in supporting ERAD. Preliminary data indicate that Kar3-Vik1 is required for efficient degradation of specific ERAD substrates and that this function is distinct from its mitotic roles. The proposed research will test the hypothesis that Kar3-Vik1 is a critical mediator of ERAD, acting at the interface of the ER and cytoskeleton. In alignment with the mission of the National Institute of General Medical Sciences, this work aims to improve understanding of how cytoskeletal dynamics influence ERAD, a cellular mechanism of significant biomedical importance, using yeast as a model. Disruption of ER PQC, cytoskeletal structure, or motor protein function contributes to overlapping spectra of human conditions, including neurodegeneration and cancer. The specific aims of this project are to (1) define the roles of Kar3 in protein quality control pathways and cellular stress responses, (2) characterize the mechanism of ERAD dependence on Kar3-Vik1, and (3) determine how microtubule dynamics and cell cycle progression impact ERAD. The requirement of Kar3-Vik1 for PQC in different cellular compartments and for fitness under diverse stress conditions will be assessed. Experiments will determine whether Kar3-Vik1 is required for substrate ubiquitylation, how Kar3-Vik1 affects the abundance of ERAD machinery, and whether Kar3-Vik1 physically associates with ER membranes. Protein interaction studies will identify Kar3-Vik1 binding partners relevant to ERAD function. Finally, structural and contextual requirements for Kar3-Vik1 activity will be defined, including identification of the domains of Kar3 and Vik1 that are required for ERAD and determination of the influence of microtubule stability and cell cycle stage on ERAD efficiency. These studies will yield novel insights into the underappreciated involvement of microtubule dynamics in ER PQC. Ultimately, this work has the strong potential to inform improved therapeutic strategies for human conditions associated with disrupted cytoskeletal dynamics and ERAD, including neurodegeneration and cancer.