University Of Texas At Austin

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY Major Neurocognitive Disorders of Aging, including Alzheimer's Disease (AD) and Alzheimer's Disease Related Dementias (ADRD), produce cognitive declines that substantially affect daily living. To date, the molecular processes underlying the neurodegeneration and cognitive declines that ultimately give rise to AD/ADRD remain poorly understood. Recent developments in genome wide association study (GWAS) provide promising avenues for identifying genetic variants and associated biological pathways of AD/ADRD risk beyond those characterized by polymorphisms within the well-known APOE gene. However, a major challenge to progress in AD/ADRD genomics is that contemporary methods used to diagnose AD/ADRDs for epidemiological research often rely on cognitive assessments or clinical rating at a single point in time, which are confounded by substantial variation in peak levels of cognitive function in early adulthood. Particularly when peak levels of cognitive function are high, cognitive declines may go undetected for decades before individuals present with impaired levels of functioning. Indeed, it has now become clear that by the time AD/ADRD diagnoses are made, the pathophysiology of AD/ADRD and trajectories of accelerated cognitive decline have accumulated extensively, during a so-called “silent period.” These issues both dilute and bias GWAS associations in conventional case-control, time-to-event, age-at-event, and single occasion designs. The primary goal of the current R01 proposal is therefore to conduct the first large-scale consortium-based GWAS of continuous rates of longitudinal aging-related cognitive change prior to dementia onset. This will allow us to identify variants beyond those in the APOE gene that confer risk for rate of cognitive decline leading to eventual AD/ADRD, estimate improved genome-wide polygenic scores that can be used to enhance assessment of AD/ADRD risk, and identify novel biological pathways of AD/ADRD risk that can be targeted by prevention and treatment efforts.

NIH Research Projects · FY 2025 · 2021-08

Program Director/Principal Investigator (Last, First, Middle): Strakowski, Stephen M. ABSTRACT Although bipolar I disorder is a dynamic condition expressing a wide range of affective, cognitive and neurovegetative symptoms, it is defined by the occurrence of mania. Mania typically first emerges in adolescence and young adulthood, and it is a strongly predictive phenotype. Moreover, the early course of bipolar I disorder is progressive, as euthymic periods shorten over time. Additionally, bipolar I disorder is strongly familial with heritability rates approaching 85%. A family history of bipolar I disorder increases risk for mania as well as a number of other psychiatric conditions, including suicidal behaviors and reward hypersensitivity. Together, these characteristics suggest that bipolar I disorder results from an inherited failure during adolescence to develop healthy neural systems that modulate mood and behavioral activation. Complicating the inherited risk is that people with a family history of bipolar disorder also report higher rates of early life adversity than the general population. Early life adversity is associated with lifelong elevated rates of depression, anxiety and substance use disorders, impaired risk-reward processing, and suicide. Consequently, during development individuals with a familial risk for bipolar I disorder may be exposed to a dual risk, i.e. an inherited vulnerability and environmental early-life stress. How these risks interact to impact brain development and subsequent outcomes in these individuals is not known. Mood and risk-reward behaviors are managed by intersecting ventral prefrontal networks. These networks undergo substantial development in the transition from adolescence to young adulthood (when bipolar I disorder emerges) in which maturation of prefrontal networks leads to adaptive adult emotional regulation and risk-reward processing. Abnormalities in these networks are commonly described in both bipolar disorder and in response to early life adversity, with many shared characteristics. With these considerations in mind, we hypothesize that heritability for bipolar I disorder interacts with early life adversity to synergistically disrupt healthy ventral prefrontal network development during adolescence, underlying a cumulative increased risk for developing mania and other conditions more common in bipolar families. To test this hypothesis, over a four-year interval we will assess trajectories in ventral prefrontal network connectivity in youth at-familial-risk for bipolar I disorder compared to those without this risk, and the interaction with or without early life trauma, to determine whether these risks cumulatively lead to increasing emergence of: 1) mood symptoms and syndromes, 2) substance misuse, 3) suicidal behaviors, and 4) approach motivation hypersensitivity. These results can inform future approaches to prevent illness onset and progression in individuals at risk for or early in the course of bipolar disorder. OMB No. 0925-0001/0002 (Rev. 03/16 Approved Through 10/31/2018) Page Continuation Format Page

NIH Research Projects · FY 2025 · 2021-08

A critical characteristic of human language is our ability to understand multi-word sequences whose meaning is greater than the sum of their parts. Recent work from the PIs of this proposal (Toneva and Wehbe, 2019; Jain and Huth, 2018) and others (Schrimpf et al., 2020a; Caucheteux & King, 2020) has shown that cortical representations of multi-word sequences can be modeled much more accurately than before by using neural network language models, a machine learning technique that has revolutionized the natural language processing (NLP) field (Devlin et al., 2019; Radford et al., 2019). However, under the current paradigm these models must first be trained on separate NLP tasks and only then used to model the brain, creating a guess-and-check cycle that is not guaranteed to converge on the actual computations that humans perform. Here we propose to break this cycle by directly training neural network models to estimate the functions that the brain uses to combine words. To be able to optimally predict fMRI and MEG responses, these models will need to capture the composition principles governing which words the brain attends to, and how information is combined across words. These models will help uncover specific computations underlying language processing in the brain, enable computational testing of neurolinguistic theories, and inspire or directly improve models used in NLP. Accomplishing these goals, however, will require overcoming one major obstacle. Training neural net- work language models typically requires orders of magnitude more data than existing neuroimaging datasets. To address this issue, one central goal of this proposed project is to collect a very large fMRI and MEG dataset comprising roughly one million words of natural language stimuli. We plan to use the unique dataset and computational modeling framework to address three scientific aims. Aim 1: Create brain activity prediction benchmarks to foster interaction between neuroscience and NLP. Aim 2: Use data-driven models to test existing neurolinguistic theories & develop new accounts of the computations underlying word composition in the brain. Aim 3: Leverage information in different brain areas to help solve computationally defined language tasks. Successful completion of the proposed work will provide mechanistic insight into language processing, with a computational architecture tracing information flow among brain areas and describing the tasks they perform. Beyond its basic cognitive neuroscience implications, we expect this work will enable better understanding of language impairments and help identify targeted therapies. RELEVANCE (See instructions): Through collecting, analyzing, and disseminating large-scale neuroimaging datasets collected while participants listen to natural, narrative speech, this proposal aims to improve our understanding of the normal function of the language system. Specifically, this work seeks to improve and validate computational models of speech language processing in the human brain.

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY: A MOLECULAR TOOLKIT FOR CONTROLLING AND PROBING CELL JUNCTION- ACTIN INTERACTIONS Higher metazoans exhibit robust, yet dynamic connections between neighboring cells, leading to the exquisite morphogenesis, vectorial transport, and resilient mechanical properties that define tissue. Spatially separated junctions line individual epithelial membranes and are tasked with linking cells to one another and to the underlying extracellular matrix. These junctions are composed of well-characterized membrane proteins, each with unique functions: claudins create paracellular barriers; cadherins bind cells together; and integrins attach cells to matrix. Despite unique classes of membrane proteins, different junctions all possess a common element, the cytoskeleton, which resides on the cytosolic side of the contact. One cytoskeletal polymer in particular – actin – appears indispensable for junction activity. While decades of elegant work have transformed our understanding of the structure and binding characteristics of junctional membrane proteins, the question of how actin is involved in cell junction formation, junction maintenance and repair, and junctional signaling remains unresolved. Actin filaments are ubiquitous throughout the cell as they contribute to cell shape, endocytosis, mitosis, motility, and other critical phenomena. However, this wide distribution presents a fundamental problem when studying actin – namely how to pinpoint the exact role actin filaments play in the process-of-interest. While actin- targeted natural products and small molecules are widely used to disrupt filaments globally, they lack the specificity needed to uncover the role of actin filaments locally at cell junctions. My research group is developing a suite of molecular tools to both control and dissect actin interactions at cell junctions. In this way, we provide researchers with new methods to turn-on and -off actin association and to probe actin’s role in adhesion and cell-cell mechanics. These tools come in various molecular forms: i) protein-based switches, ii) small-molecule molecular glues and inhibitors, and iii) synthetic cells, which can be applied to wide-ranging systems, such as reconstituted membranes, cells, monolayers, tissues, and organisms, to illuminate and manipulate actin- dependent processes. In my lab, we will harness these molecular tools to focus on three specific research directions in epithelial biology, although we anticipate that the toolkit will benefit the greater biological community, including biochemists, cell biologists and developmental biologists. First, we will focus on applying our tools to dissect actin’s role during tight junction maturation and, ultimately, to modulate barrier function. Second, we will investigate, in mechanistic detail, how actin potentiates integrin activation during focal adhesion formation. Finally, we will assemble cells using actin switches to generate “synthetic tissues” with programmable and toggleable properties, such as dynamic tissue permeability and adhesion. Broadly, this research program relies on our diverse expertise in molecular engineering, basic membrane biology, and translational science to create a virtuous cycle of innovation and discovery over the course of the MIRA award.

NIH Research Projects · FY 2025 · 2021-08

PROJECT SUMMARY Urbanization, migration, and the nuclearization of households are changing the family context into which children are born. Health at birth is not only determined by economic circumstances: the social support and social status of mothers in their family contexts are embodied in the health of pregnancies, with consequences for lifelong wellness. However – and despite the importance of social circumstances for public health – because prior population science has lacked the population-level biomarkers needed to understand these processes – a comprehensive understanding of family structure, stress in pregnancy, and health at birth has not previously been possible. In this mentored project, PI Diane Coffey will pursue training in the biomarkers and biological processes of stress in pregnancy. Training in population-level biomarker data and stress biology will empower her career as an independent population scientist studying healthy pregnancy as a start to lifelong wellness. The project has three specific aims. Under Aim 1, Coffey will receive mentored training in the use of biomarkers in population-level survey data on pregnant women (blood pressure, obesity, glucose, and hemoglobin), in the biomarkers (cortisol, CRP) and biology of stress in pregnancy, and in biostatistics. She will complete an extensive program of coursework and guided reading and attend workshops and conferences on biomarkers. Aim 2 is for the PI to conduct within-population studies of consequences of household structures for biomarkers of stress in pregnancy and birth outcomes. One part of Aim 2 will study the importance of three-generation households; another part will investigate the consequences of partner absence. Aim 3 is to construct comparisons and inform theory by comparing outcomes in settings with different social environments for pregnant women. Achieving these three aims will prepare the PI to apply for future R01 support as an independent population scientist. The resulting research agenda will add new biosocial root causes to existing models of early life health.

NIH Research Projects · FY 2025 · 2021-07

Project Summary/Abstract Although there is much hope for an effective vaccine to combat COVID-19, a pressing need remains to develop direct acting antivirals in the event that vaccines fail to provide protective immunity, for the treatment of acute infections, and for future coronavirus strains that might evade existing vaccines. The SARS coronavirus (CoV- 2) RNA-dependent RNA polymerase (RdRp) is an attractive target because inhibitors of viral RNA-dependent polymerases form the cornerstone of antiviral drug combination therapy for successful treatment of HIV and hepatitis C virus infections. Remdesivir, a nucleotide analog developed by Gilead, is already showing promise in clinical trials. The long-term goal of this research is to facilitate the development of more effective, less toxic drugs directed against the SARS CoV-2 RdRp. The rationale for this research is based on prior experience demonstrating that accurate measurements of the kinetics of nucleotide incorporation and excision by the viral polymerase/exonuclease translates directly to understanding viral RNA replication and can guide the design of robust assays to find effective inhibitors. Kinetic analysis will be based on single turnover rapid-kinetic measurements of polymerization to provide definitive results to define the mechanistic basis for nucleotide selectivity. Our working hypothesis is that an effective nucleotide analog can be identified and its therapeutic potential quantified based on analysis of the kinetics of incorporation relative to the kinetics of excision by the proofreading exonuclease. Specifically, the aims of this research are to quantify the kinetics of nucleotide incorporation using single turnover kinetic analysis in order to establish the mechanism and overall fidelity of the RNA replication. Parallel studies will establish the kinetic and mechanistic basis for inhibition for nucleotide analogs. We will also include extensive characterization of the kinetics of the proofreading exonuclease to define the rules governing removal of mismatched base pairs and nucleotide analogs. We will also us cryoEM with samples based on our biochemical knowledge to obtain structures of the polymerase with Remdesivir incorporated and of the RdRp with the exonuclease. These studies are innovative in that they take advantage of the most advanced methods of single turnover kinetic analysis and global data fitting developed by the PI to establish the kinetic and thermodynamic basis for polymerase specificity to reveal the basis for discrimination against nucleotide analogs. No other lab is applying such standards to this important problem. Moreover, this quantitative analysis provides an accurate vector pointing toward more effective inhibitors in structure/activity relationship studies. The work is soundly based the the PI's prior work and on preliminary data explaining the kinetic basis for the effectiveness of Remdesivir in competing with ATP. The proposed research will significantly advance our understanding the mechanism and kinetics of CoV RNA replication and provide a sound quantitative basis to find inhibitors acting directly against viral replication. This research has a strong potential to play a key role in the developing direct acting antiviral drugs to combat SARS CoV-2 and future coronaviruses.

NIH Research Projects · FY 2025 · 2021-07

Project Summary Despite widespread use of a vaccine, infection with the bacterium Bordetella pertussis continues to claim the lives of ~200,000 infants annually worldwide and cause significant morbidity and mortality in developed countries, including the US. To develop improved vaccines and therapeutics, we need to better understand how this organism causes disease and identify new vaccine antigens. The adenylate cyclase toxin (ACT) is a leading candidate for inclusion in future pertussis vaccines. ACT is a large (1706 residue), bi-functional toxin with a cell- invasive domain fused to a pore-forming repeat-in-toxin (RTX) hemolysin domain. The RTX domain is composed of five blocks of ~8 nonapeptide motifs separated by linkers of different length and sequence. ACT efficiently targets leukocytes by binding αMβ2 integrins via a site localized to the RTX domain. Receptor binding triggers translocation of the 40 kDa N-terminal adenylate cyclase domain across the host cell membrane where it rapidly converts nearly all intracellular ATP to cAMP, thereby compromising phagocytic and other leukocyte anti- bacterial activities. Although the general features of ACT function have been described, there are few data to support a molecular understanding of any step in the intoxication process for ACT specifically or for RTX proteins more generally. The structural features by which the RTX blocks mediate specific protein–protein interactions, such as receptor binding, and the epitopes and mechanisms by which antibodies inhibit ACT function are not well defined. Our panel of high-affinity antibodies that recognize neutralizing and non-neutralizing epitopes on ACT provide a unique opportunity to address these questions. The long-term goal of this research is to understand structural mechanisms of the complex cellular intoxication process used by the Bordetella adenylate cyclase toxin to incapacitate immune cells. The specific objective is to provide a molecular description of the interaction of ACT’s RTX domain with its receptor and with neutralizing and non-neutralizing antibodies. This will provide mechanistic insights into ACT function and define important vaccine targets such as epitopes susceptible to antibody-mediated neutralization, the receptor-binding site, and pre-translocation conformations. Such information is necessary for the implementation of rational design strategies that seek to more effectively present such targets to the immune system. The expected outcomes include the first structures of an RTX protein containing more than two repeat blocks and the first RTX–antibody and RTX–receptor structures. We will also evaluate structural pathways for RTX antibody escape and species specificity and the impact of such changes on cellular toxicity of the intact ACT protein and bacterial infection using a mouse model. Since there are currently no structural data defining antibody or receptor epitopes for any RTX protein, this work will transform our understanding of this class of bacterial toxin and provide insight into a key pertussis virulence factor.

NIH Research Projects · FY 2025 · 2021-07

Our proposed predoctoral training program “Problem-to-Product Team Entrepreneurship and Active Mentoring” (P2P-TEAM) cultivates a team science approach to research training, with an emphasis on entrepreneurial skills and professional development. The program will train the next generation of students to flourish in scientific teams and embrace an entrepreneurial perspective that will benefit the many graduate students in STEM fields who transition into industrial careers, as well as those pursuing academic or government career paths. The program revolves around the formation of interdisciplinary teams, which serve as the nuclei for pursuing advanced research projects related to the overarching theme of theranostics, a new approach to personalized medicine combining targeted therapy and diagnosis. The program will engage students in team-based collaborative projects and encourage entrepreneurial efforts that build directly from translational impact (i.e., prospects for technology transfer and commercialization). The team-based collaboration model is designed to increase accountability, develop peer networks and support systems, and motivate students to see their individual research efforts in the context of solving bigger problems with potentially translational payoffs, while the emphasis on entrepreneurship is designed to foster innovation and develop an understanding of the business world and industry practices. The program is planned for two trainees in the first year, then a steady-state of five trainees in subsequent years. The duration of each appointment is 2 years. Key programmatic features of the P2P-TEAM program include (i) collaborative research, (ii) entrepreneurial training, and (iii) professional development. The training program has 5 overarching goals: (1) facilitate the development of interdisciplinary peer teams, (2) improve scientific communication, (3) encourage an entrepreneurial perspective and business acumen not typically fostered in traditional graduate programs, (4) develop project management skills, and (5) enhance professional training (soft skills). Specific activities include training in translation of research problems into products; participation in professional development, statistical informatics, and entrepreneurship courses; activities to build networking and scientific communication skills; creation of an annual prospectus; and engagement in industrial internships. Industrial mentors will provide insight into the business aspects related to assessment of technology development arising from the collaborative research projects. The frontier field of theranostics provides avenues for both basic and applied research projects, as well as natural translation to commercialization opportunities, making it an ideal focus of the proposed training program. Because of its interdisciplinary and translational research approach, our program will be an avenue for recruiting and retaining highly innovative graduate students.

NIH Research Projects · FY 2025 · 2021-07

PROJECT SUMMARY The overall goal of the proposed research is to understand the role of Twist1 in cutaneous squamous cell carcinoma (cSCC) and to develop novel approaches for targeting Twist1 for prevention and treatment of this important disease. Twist1 is a transcription factor involved in epithelial-mesenchymal transition and cancer progression and metastasis in a number of epithelial cancers. In previous studies from our laboratory, we found that Twist1 was required for proliferation of keratinocytes during the process of skin tumor promotion by TPA suggesting a role early in the process of skin carcinogenesis in addition to its role in cancer progression and metastasis. These earlier studies showed that Twist1 regulated levels of G1-S-phase cell cycle proteins. Furthermore, Twist1 was shown to regulate the function of p53 and p21. To date, the impact of Twist1 on UV skin carcinogenesis has not been studied and therefore it is important to demonstrate that Twist1 also plays critical role in UV skin carcinogenesis. In new preliminary experiments, we have found that deletion of Twist1 in keratinocytes leads to keratinocyte differentiation. Furthermore, deletion of Twist1 in basal keratinocytes of mouse epidermis in vivo leads to changes in bulge-region keratinocyte stem cells (KSCs), including migration of KSCs out of the bulge region. These findings suggest that Twist1 may play an important role in regulating keratinocyte differentiation and be required for KSC homeostasis. In additional preliminary experiments, we have found that Ovol1 expression is significantly upregulated in Twist1 deficient keratinocytes and may be responsible for driving differentiation. Furthermore, we have also found that Harmine, a naturally occurring compound reported to inhibit Twist1 by facilitating its degradation, induces differentiation in keratinocytes and upregulates Ovol1 in a manner similar to that seen in epidermis of Twist1 KO mice. In this proposal, we will test the hypothesis that Twist1 plays a critical role in UV-induced cSCC by maintaining the balance between proliferation and differentiation of epidermal keratinocytes, including KSCs via regulation of the levels of Ovol1 and that targeting Twist1 will effectively inhibit UV-induced cSCC. The specific aims are as follows: i) To further examine the role of Twist1 in regulating proliferation and differentiation of keratinocytes and KSCs; ii) To examine the impact of keratinocyte specific deletion of Twist1 on UV-induced skin carcinogenesis; iii) Determine the role of Ovol1 as a downstream effector of Twist1 in regulating proliferation and differentiation of keratinocytes and KSCsand iv) Further evaluate the ability of Harmine, a novel Twist1 inhibitor, to prevent UV- induced skin carcinogenesis. Completion of the proposed studies will further elucidate the role of Twist1 in keratinocyte and KSC proliferation and differentiation and its role in development of cSCC, especially in the early stages of skin tumor development. Identification of Twist1 as a key early player in skin cancer development could lead to novel approaches for the prevention and treatment of cSCC. Development of novel agents for prevention and/or treatment as proposed in this grant application could lead to rapid translation of such agents into the clinic.

NIH Research Projects · FY 2025 · 2021-07

PROJECT SUMMARY All complex eukaryotes rely on mitochondria to generate the cellular energy needed to maintain proper organismal function. Mutations in the mitochondrial genome underly multiple diseases and have been suggested to play a general role in aging. However, understanding the causes and consequences of mitochondrial mutations is limited by a focus on mammalian models. We will characterize mitochondrial mutations and their effects on physiology in diverse eukaryotic systems, including invertebrates, plants, and micro-eukaryotes. We will address three challenges that have hindered our understanding of mitochondrial mutations. First, we will use high-fidelity sequencing to characterize rates and types of mitochondrial mutations across eukaryotes and under different environments (e.g., increased oxidative stress), resulting in a “mitochondrial mutation atlas”. Of particular interest is the frequency of C -> T transitions resulting from replication errors vs. G -> T transversions characteristic of oxidative damage. The latter are implicated in aging theories, but the former have been shown to dominate the mutational landscape in mammalian mitochondrial genomes. Second, we will quantify distinct states of oxidative phosphorylation, reactive oxygen species (ROS) production, and metabolic rate in systems with varying sources and rates of mitochondrial mutations to determine how mutations affect organelle and organismal traits. We will also explore a mechanistic link between oxidative stress and mitochondrial mutations by increasing ROS via superoxide dismutase knockdown. Third, we will examine mitonuclear protein and transcript balance in two lineages where closely related organisms have disparate lifespans: rockfishes and cave salamanders. A shift towards reduced mitochondrial protein abundances has been identified as a conserved mechanism of longevity in long-lived strains of mice and nematodes, but it is unknown if natural long-lived populations have altered mitonuclear protein balance. We will also quantify mitochondrial mutations and physiology in these species to determine how natural selection may have shaped aging through mitochondrial processes. Overall, this research will provide a complement to previous work on mammalian models, which show uniformly high mitochondrial mutation rates. It will further uncover the possibilities for mitochondrial mutations to influence cellular and organismal processes, with implications for human health, disease progression, and aging.

NIH Research Projects · FY 2026 · 2021-06

Project summary/Abstract The overall goal is to develop novel tools to advance spatial metallomics, spatial metabolomics, genome editing, and biocatalysis by designing and selecting DNAzymes, DNA aptamers, and biosynthetic models of heteronuclear metalloenzymes involved in multi-electron and multi-proton processes. In the first project, we plan to develop super-resolution imaging methods to map metal ions and metabolites at nanometer resolution in vitro and in vivo based on DNAzymes and aptamers that are highly selective for metal ions and metabolites. To achieve three-dimensional ratiometric mapping of metal ions and metabolites in living cells and mouse tissues, we will develop specific nucleic acid intramolecular ligation (SNAIL) probes for DNAzymes and aptamers. Additionally, we will introduce electrophilic sulfonyl fluoride-modified DNAzymes and aptamers to understand metal ion/metabolite interactions with proteins. These advancements will address critical challenges in spatial metallomics and metabolomics, bringing our understanding of metal ion and metabolite distributions to the same level as spatial transcriptomics.. In the second project, we seek to establish an alternative genome editing strategy to CRISPR/Cas by integrating peptide nucleic acids for targeted double-stranded DNA opening and DNAzymes engineered for precise DNA cleavage under physiological conditions. This approach promises to overcome current CRISPR/Cas limitations, offering greater sequence fidelity, expanded gene accessibility in compacted genome regions, and reduced immunogenicity. Finally, we will design biosynthetic models of nitric oxide reductases (NORs), heme-copper oxidases (HCOs), and heme-copper sulfite reductases (SiRA) using small, stable protein scaffolds. By refining existing models, identifying alternative scaffolds from the Protein Data Bank, and employing generative protein design methods, we aim to gain a holistic understanding of the structural features that enable efficient and selective 2-, 4-, and 6- electron catalytic reduction of NO, O2, and SO32-, respectively.

NIH Research Projects · FY 2025 · 2021-04

Although critical for development, the placenta is one of the least understood organs in the body. Cells belonging to the trophoblast lineage mediate proper implantation and placentation as well as the hematopoietic, vascular, and immunological properties of the placenta. Defects in proper trophoblast differentiation cause early pregnancy failure and other pregnancy-related disorders, but the molecular mechanisms of human trophoblast differentiation remain poorly understood. So far, only a few transcription factors (TFs) are known to play important roles in trophoblast lineage specification, and their functions are primarily characterized in mice, not human. Furthermore, how these TFs form global gene regulatory networks with other regulators, or their target cis-regulatory elements is not well understood. The objective of the proposed research is to delineate transcriptional regulatory networks and global regulatory logics modulating trophoblast lineage differentiation by utilizing human trophoblast stem (TS) cells and their differentiation towards syncytiotrophoblast (ST) and extravillous cytotrophoblast (EVT) as model systems via systems and molecular biology approaches. We hypothesize that mapping trophoblast cell-specific enhancers will allow us to define novel key TFs that control the self-renewal and differentiation of human trophoblast lineages. Our preliminary studies in both mouse and human TS cells revealed that most previously known trophoblast lineage markers are located close to enhancer clusters (ECs) that we have mapped in each cell type, supporting our hypothesis. Our objectives are to 1) comprehensively define human TS cell, ST, and EVT- specific enhancers and ECs, and subsequently identify EC-associated putative key regulatory TFs, 2) functionally validate putative key TFs in self-renewal and differentiation of TS cells to ST and EVT in vitro and in vivo, and 3) reconstruct the core transcriptional regulatory networks modulating human TS cells, ST, and EVT by mapping both native protein interacting partners and chromosomal targets of key TFs. Our proposed studies will provide critical new data in this field, enable a systems-level understanding of early trophoblast differentiation, and create an important resource to gain further insights into the molecular regulatory mechanisms of how extra-embryonic cells are specified, maintained, and lineage-restricted during human development. Our results will help guide future biomedical advances for detecting and treating pregnancy- related disorders.

NIH Research Projects · FY 2026 · 2021-02

Summary Abstract: Intrinsic disorder as an organizing principle for cellular membrane remodeling Membrane curvature plays an essential role in cellular processes, from vesicle traffic to cell motility.1,2 Consequently, defects in membrane curvature impact many human diseases, from altered recycling of receptors in cardiovascular3 and neurological disease4 to metastasis of tumor cells5 and defects in wound healing.6,7 How do cells create curved membrane surfaces? Research has primarily focused on individual protein domains with specialized structures, such as crescent-shaped scaffolds8,9 and wedge-like amphipathic insertions.10,11 However, these domains often exist within proteins that also have large intrinsically disordered regions.12–14 Far from being passive, these disordered regions mediate the assembly of flexible protein networks at sites of membrane curvature.15 During the past 5 years, our group has made pioneering discoveries suggesting the hypothesis that flexible protein networks drive membrane curvature by balancing attractive and repulsive interactions.15–29 Specifically, we showed that flexible protein networks use attractive interactions to concentrate key proteins, driving the assembly of clathrin-coated vesicles, while simultaneously using repulsive interactions to promote departure of mature vesicles.16–18 Similarly, to facilitate actin bundling, a key step in membrane protrusion, we showed that flexible protein networks use attractive interactions to amplify repulsive mechanical stresses.19–21 Collectively, this work has illustrated that the role of each protein in membrane remodeling can only be understood in the context of the network of other proteins with which it interacts. This innovative perspective raises a key question – how do cells use flexible protein networks to create curved membrane structures, while avoiding off-target outcomes? To address this question, we will examine key inwardly and outwardly curved structures at the plasma membrane. First, we will examine inwardly curved clathrin-coated vesicles, determining the balance of attractive and repulsive interactions required for efficient endocytosis that neither aborts prematurely nor stalls indefinitely. Second, we will examine outwardly curved filopodia, finger-like, actin-filled protrusions. Here we will determine how a flexible protein network bundles actin filaments, achieving the rigidity required to bend the membrane, without becoming too rigid to respond to environmental changes. Third, we will investigate how inwardly curved endocytic structures and outwardly curved filopodia compete for a shared pool of transmembrane proteins. Here we will determine how disordered protein networks and post-translational modifications work together to ensure that each structure incorporates the correct molecular cargo, while leaving off-target proteins behind. Collectively, by elucidating the role of flexible protein networks during both inward and outward curvature induction, our work will shift the paradigm for understanding membrane curvature beyond its present focus on in vitro structure-function relationships toward an understanding of flexible, multi-valent protein interactions during dynamic cellular processes.

NIH Research Projects · FY 2025 · 2021-01

PROJECT SUMMARY. Pathologies characterized by excessive fear and anxiety are the most common mental illness with a 12-month prevalence estimate of about 40 million American adults. The primary treatment for anxiety and stress-related disorders is exposure therapy, which is informed by theoretical and technical aspects of Pavlovian extinction. However, extinguished behaviors are prone to relapse under a variety of circumstances. Further, clinical research reveals serious deficits across a host of psychiatric conditions in the ability to form and retrieve extinction memories, which likely contributes to relapse following extinction-based therapies. Accordingly, there is strong motivation to better understand how extinction memories are encoded, stored, and expressed so as to bolster the strength and generalization of clinical treatment. Pioneering research in rodents reveals that fear conditioning and extinction generate separate and measurable memory traces within and across discrete brain regions. Whether such an organization exists in the human brain is unknown. More precise knowledge on how threat and safety memories are represented and interact in the human brain will advance innovative treatments for pathological anxiety that are built on the neuroscience of learning and memory. The goal of this research is to better understand how competing memories of fear and safety are formed, stored, and retrieved in the human brain. To build directly on mechanistic insights from animal models, we utilize Pavlovian fear conditioning and extinction in adult humans during functional magnetic resonance imaging (fMRI). The research leverages advances in multivariate pattern analysis techniques, and integrates theoretical and technical advancements of fear extinction research from animal models with computational approaches developed to study human memory. Each study includes healthy adults and individuals with posttraumatic stress disorder (PTSD), as linking advances in fear extinction research to the pathophysiology of PTSD can have direct benefit to exposure therapy—the gold-standard treatment based on the principles of extinction. We also evaluate extinction memory at 24-hours and again at 1 month. Assessing long-term extinction retrieval in humans is extremely rare, but consistent with diagnostic criteria for assessing PTSD, and thus furthers the bridge to translational relevance. Aim 1 attempts to identify separate and stable memory traces of fear and extinction in by identifying the correspondence (overlap) between neural activity related to the formation and retrieval of fear and extinction over time. Aim 2 decodes a multivariate neural signature selective to the contextual encoding of extinction memories. Aim 3 uses a non-pharmacological behavioral strategy to modulate the strength of extinction to determine how enhanced fear extinction affects multivariate neural signature of extinction memory retrieval over time. These findings have the potential to establish new risk and resilience factors for anxiety and stress-related pathologies, and may ultimately contribute to innovative neuroscience-based treatments for psychiatric conditions marked by excessive fear and the inability to regulate unwanted emotional responses.

NIH Research Projects · FY 2025 · 2021-01

Abstract. Understanding the functions of lipids, proteins and even larger macromolecular assemblies depends on deciphering complex structures of individual molecules as well as decrypting how those molecules interact, often via networks of non-covalent interactions. In order to advance the elucidation of biomolecular organization and functional outcomes, new methods are needed to push the limits of structural insight, providing more detailed holistic chemical information with greater sensitivity. The critical interplay between structure/function is evidenced in numerous biologically-motivated problems, ranging from understanding the ways that pathogenic bacteria develop antibiotic resistance to the design of new drugs that selectively bind and inhibit the functions of protein targets. The ongoing need for even greater chemical insight has motivated my group’s effort to develop innovative mass spectrometry methods to characterize structures of biological molecules in unprecedented detail, especially lipids and proteins which are featured in this proposal. The overarching goal of my research program is to develop state-of- the-art tandem mass spectrometry technologies, particularly highlighting ultraviolet photodissociation (UVPD) and hybrid MS/MS methods, for structural elucidation of lipids, proteins, and protein complexes. These new methods will be showcased for solving challenging problems in three areas. (1) Lipids: (i) profiling lipids of pathogenic bacteria and their signatures of antibiotic resistance, and (ii) structural characterization of unsaturations, oxidations and other modifications of lipids that occur during remodeling of cellular membranes. (2) Protein complexes: (i) characterization of protein-ligand complexes, membrane protein complexes, protein/nucleic acid complexes, and macromolecular assemblies, and (ii) advancing capillary electrophoresis for native separations and exploration of the interactome. (3) Post-translational modifications: focusing on decoding the phosphorylation patterns of the C-terminal domain of RNA polymerase II which regulates transcription. These high impact problems are supported via numerous collaborations with microbiology and molecular biology groups who recognize the value of frontier mass spectrometry strategies for elevating biomedical research.

NIH Research Projects · FY 2024 · 2020-12

The abundant neuronal protein α-synuclein, which is implicated in neurodegenerative disease, adopts a wide variety of conformational states that contribute to its physiological and pathological activities. We recently used deep mutational scanning to probe the conformation of α-synuclein that drives its toxicity in a cellular model, and surprisingly, we found that this aberrant phenotype is driven by a dynamic, membrane-bound amphiphilic helix, which is also believed to mediate its native physiological role in vesicle trafficking. How does the physiological conformation of α-synuclein contribute to pathology? Our data highlight a critical sequence feature of α-synuclein that we hypothesize mediates both its physiological and pathological interactions with lipid membranes by increasing dynamics of the membrane-bound helix. In this proposal, we will test our hypothesis for the molecular basis of helix dynamics, as well as the contribution of those dynamics to exocytosis and aggregation. In order to test these hypotheses, the principal investigator (PI) requires additional training in nuclear magnetic resonance (NMR) spectroscopy, mammalian cell culture and manipulation, and cellular imaging, as well as additional expertise in membrane protein biophysics and the molecular biology of vesicle trafficking and neurotransmission. These hypotheses will therefore be addressed under the mentorship of Prof. William DeGrado, one of the world’s leading experts in membrane protein structure and function, and Prof. Robert Edwards, one of the world’s leading experts on the role of α-synuclein in exocytosis. With their guidance, the PI will (1) test the contribution of α-synuclein sequence features to the dynamics of the membrane bound state using NMR spectroscopy, and (2) test the role of those sequence features in mediating α-synuclein’s effect on exocytosis in neuroendocrine cells. Following completion of the mentored phase, the PI will (3) test the contributions of dynamic membrane binding to α-synuclein aggregation using deep mutational scanning. Together, these aims will provide a molecular mechanism by which the unique structure of α-synuclein contributes to both its physiological and pathological activities. Moreover, the training provided by these experiences will position the PI to launch an independent scientific career examining functional interactions between proteins and lipid membranes, as well as the biophysical and cellular determinants of protein misfolding.

NIH Research Projects · FY 2025 · 2020-12

ABSTRACT To understand speech, the human brain must parse and transform a noisy acoustic signal into meaningful linguistic content, including phonemes, syllables, words, and sentences. This involves determining the timing of important acoustic events, such as the onset of a sentence or a phrase. Following detection of these onsets, the content of the sentence must be determined. The posterior superior temporal gyrus (pSTG)—including the classic “Wernicke’s area”—is critical to this process, but until recently, little was known about its functional organization, and in particular how this functional organization changes throughout development. Our recent work showed that a spatially discrete region of the pSTG is critical for indicating when a sentence or phrase begins. This region is distinct spatially and functionally from more anterior “sustained” areas that encode phonetic feature information throughout a sentence. Functionally, both posterior onset and anterior sustained regions show short and long temporal integration times, respectively, suggesting complimentary roles in natural speech processing. Here, we propose an innovative approach using rare datasets where neural activity is recorded directly from the human auditory cortex and speech-related areas in pediatric patient participants undergoing clinical evaluation for epilepsy surgery. This method overcomes the spatial and temporal resolution limitations of other noninvasive procedures, and provides a rare window into the function of the human auditory cortex. The proposed study will use high resolution intracranial recordings to investigate how the brain detects acoustic onsets in natural speech sound mixtures, and how neurophysiological responses to these sounds change from early childhood to adolescence. Furthermore, we will investigate how these responses to onsets are modulated by context, including during attention and for self-generated sounds. In addition to providing insight into the basic functional organization of the human auditory cortex and cortical mechanisms for auditory scene analysis, this research has important implications for the development of a speech brain computer interface. Our results could also inform how speech and language are processed in natural contexts, which has implications for the treatment of developmental language disorders, auditory processing disorder, dyslexia, autism, and aphasia.

NIH Research Projects · FY 2025 · 2020-09

Project Summary In the United States and around the world, people are living longer lives. As the population ages, so does the number of older adults who may experience declines in memory, attention, reasoning, or other thinking skills. Some of these changes in cognition can be treated and reversed if caught early. Others can be slowed down and hopefully one day prevented. Unfortunately, people with cognitive decline or very mild dementia often are not recognized until late in the disease course when treatments are less effective. As the first health care professional most people reach out to about medical concerns, primary care providers play a critical role in detecting cognitive decline early. While many primary care providers conduct cognitive screening at Medicare Annual Wellness Visits and when patients voice concerns, 9 out of 10 would like more information about who to screen, which assessment tool to use, and what to say if screening is positive. Deciding who to screen with a brief cognitive assessment tool is a key part of the process because not everyone needs to be screened, and primary care providers already face time pressures to address the obvious and immediate concerns of their patients. The long-term goal of this project is to develop a risk assessment and cognitive screening tool that requires minimal time and effort from primary care providers or their staff and is sensitive to cognitive decline in older adults from diverse educational and racial/ethnic backgrounds. The tool will be integrated into electronic health record systems to make it easy for primary care providers and patients to see results. The specific aims of the first phase of the project are to modify an existing dementia risk screening index to identify older adults who are at high-risk for cognitive impairment, develop a brief cognitive assessment tool using tasks that are easy for older adults to perform yet are sensitive to cognitive decline, confirm their utility in 150 people with varying levels of cognitive abilities that have already been well defined, and test ways to integrate findings into the electronic health record. The specific aims for the second phase are to further test the effectiveness of the newly developed tool in 250 older adults receiving care in a primary care clinic, to find out from primary care providers using the tool how much they liked it and if it was useful and easy to use, and to integrate findings into multiple electronic health record systems. Findings from this project will fill a gap in the existing toolkit of primary care providers and will make screening for cognitive decline quick, easy, and effective.

NIH Research Projects · FY 2024 · 2020-09

PROJECT ABSTRACT Although hydrogel-based materials constitute a multibillion-dollar market, commercial applications for drug delivery and regenerative medicine are extremely limited. Hydrogels have garnered intense interest as extracellular matrix (ECM) mimics due to their tailorable permeability, mechanics, and degradability, yet their clinical use in this area largely depends on biological materials such as proteins. Although some success has been met with naturally-derived ECM, these naturally derived materials are often limited by long regulatory approval timelines due to the potential to react with other biologics. Synthetic materials are therefore attractive due to their known chemical compositions, but the challenge with their use lies in the lack of complexity as compared to biological systems, which translates to a lack of efficacy in the clinic. Hence, the goal of this proposal, and of our research lab, is to expand the toolbox for building complexity and functionality into synthetic hydrogel biomaterials by using dynamic chemistries and monomer sequence-based strategies. This strategy takes much inspiration from nature, as the structure and function of biological polymers arise from the precise placement of their amino acids or nucleotides. In addition, cells are able to remodel and reconfigure the natural ECM over time. Both of these characteristics have proven difficult to engineer into synthetic networks. Hence, our goals over the next five years are to 1) develop hydrogels with reversible crosslinks to quantitatively design reconfigurable matrices, 2) develop synthetic sequence-controlled linkers to control hydrogel properties (e.g., mechanics, degradation, activity) using polypeptoids, and 3) combine these approaches to develop self-assembled constructs for tissue engineering. We believe our goals will be useful for broad applications in regenerative medicine, therapeutic delivery, and preclinical models of tissue for drug development. In addition, we anticipate that the potential to alter current modes of thinking in hydrogel and biomaterial design is high, and that our work will shed insight to the biological processes underlying cell-matrix interactions. For these reasons, this work is well suited for the R35 Maximizing Investigators' Research Award for Early Stage Investigators.

NIH Research Projects · FY 2025 · 2020-09

Central sensitivity syndromes (CSS), including Fibromyalgia (FM), are common and difficult to treat disorders. The diagnosis of FM depends on the presence of chronic widespread pain along with concurrent central sensitivity symptoms and absence of an alternative diagnosis. The gold standard for identification of this neurologic disorder is positive affirmation of diagnosis by a rheumatologist. FM makes up a high percentage of chronic non-malignant pain conditions which are a major burden on U.S. health care resources. In large chronic pain cohorts, over 40% meet ACR criteria for FM. Thus, individuals affected with FM and other CSS make up a substantial proportion of the population receiving opioids. Accurate identification of subjects with FM and other CSS is urgently needed in order to avoid inappropriate administration of opioids and the danger of chronic opioid treatment in at risk populations. Our proposal is innovative in both its theoretical underpinnings and methodological approach of examining spectroscopic analyses as a diagnostic adjunct in well characterized FM patients while utilizing both subjective and objective monitoring. These proposed studies can lead to evidence based alternative therapy for this population. The scientific premise is based on the knowledge that non-targeted fingerprinting approaches have been shown to have a role in identifying FM patients relative to other conditions including Rheumatoid Arthritis (RA), Osteoarthritis (OA), Systemic Lupus Erythematosus and normal controls (NC). We now seek to determine the extent to which vibrational (infrared and Raman) spectroscopy technology and supervised pattern recognition analysis (“chemometrics”) can be honed to further differentiate FM subsets and pair this approach with complementary metabolomics by LC-MS/MS to identify pharmacologic targets of interest for this condition that suffers from a lack of reliable therapeutic options. During the R61 Phase we will (Aim 1): Determine the clinical reliability of bloodspot-based biomarkers to differentiate subjects with FM from individuals with OA, CLBP (Chronic Low Back Pain), RA, SLE and NCs by vibrational spectroscopy techniques. We will use multiple validated assessment instruments to grade disease severity. (R61 Aim 2): Determine the robustness of bloodspot-based biomarker. (R61 Aim 2b): Investigate the effect of intra- and inter-assay variability, and storage conditions on biomarker reliability using known independent (not used in developing the calibration model) data sets of subjects from all groups. (R61 Aim 3): Evaluate the metabolic profile of the biological samples from our subjects. Chemometric analysis of the unique spectral patterns permits determination of bands most responsible for differentiating test subjects. During the R33 Phase: (Aim 4): Distinguish FM activity (flares) relative to quiescent phases of FM. Determine changes in disease activity in patients between baseline and subsequent follow up visits of each patient. The culmination of these aims will clarify the diagnosis of FM, the most frequent neuropathic disorder encountered in clinical medicine, will help alleviate unnecessary medical testing and will serve as a deterrent to opioid prescribing in this at risk population.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY In recent years, improvements in diagnosis and treatment have extended the lives of many patients with triple negative breast cancer, but resistance to treatment remains a major clinical and scientific challenge. While standard-of-care treatment and chemotherapy is effective in many TNBC patients, approximately 40% of patients display resistance, leading to poor overall survival. TNBC are characterized by significant intratumor heterogeneity, which further complicates treatment. Mechanisms of chemoresistance in TNBC patients remain poorly understood, in part due to a lack of available methods and models to measure intratumor heterogeneity and track changes in heterogeneous tumor compositions over time. Here we propose to use a new technology to track individual cells and clones as they respond to different chemotherapeutic agents; this more detailed information about the tumor cell population will be used to build mathematical models better predict and optimize therapeutic response. We first measure individual cell gene expression changes in response to treatment and then assemble these measurements into cell subpopulation trajectories, taking advantage of a barcoding technology developed in our lab to quantify clonally-resolved single cell transcriptomes. These Aim 1 studies will build a compendium of gene expression, cell growth and survival data that describes how each of the heterogeneous cells in major experimental models of subtypes of triple negative breast cancer responds to clinically-relevant therapeutic agents. The new ability to layer clonal identifier information on single cell gene expression data reveals the detailed trajectories of individual cells that escape therapy. It also distinguishes subpopulations with pre-existing treatment resistance from those in which a resistant state is induced. At a higher conceptual level, this proposal seeks to also address a broad practical challenge: the high-dimensional ‘omics’ data collected in many large-scale efforts points often points to correlations in disease progression but not been informative for building mechanistic models to aid in the predictive of tumor response. Often, other types of data are more readily available-- lower dimensional data with more frequent measurements. We therefore next ask: How can these distinct data types be integrated into a useful framework to build predictive models of tumor cell response to therapy? This seems a fitting goal for the systems biology of cancer community. We propose to tackle this challenge with our barcode tracking technology; relative fractions of sensitive and resistance phenotypes, along with separate longitudinal measurements of cell number (low dimension data), become the inputs for a mechanistic model to predict therapeutic response and resistance (Aim 2). In Aim 3, we will perform trajectory-mapping and model testing using patient-derived triple negative breast cancer cells, towards understanding the potential for translational utility. By integrating different data types into a cohesive framework, we aim to describe how sensitive and resistant subpopulations in TNBC grow, die, and transition in response to treatment.

NIH Research Projects · FY 2024 · 2020-09

My laboratory is interested in understanding the regulation of gene expression at the molecular level. Our primary tool is cryo-electron microscopy (cryo-EM). We use cryo-EM to study the atomic details of snapshots of our macromolecular machines of interest in action. We have revealed exciting insights into the structure and function of macromolecular machines and assemblies involved in (1) protein production and (2) genome editing. We will continue to apply cryo-EM as well as other tools in our repertoire, including site-specific labeling and conformational analysis using negative stain EM, to produce mechanistic insights into the structure and function of macromolecular machines involved in gene regulation, broadly-defined. In the next five years, my lab plans on elucidating the molecular architectures that set the foundation for accurate gene expression and production of proteins, the workforce of the cell. Combined with the work on CRISPR genome-engineering complexes, these results will have major implications for researchers performing translational research to combat a myriad of diseases.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY/ABSTRACT. Violence in the United States is the third leading cause of death for young people (aged 10 to 24 years), and violent acts have immediate, enduring, and disturbing impacts on individuals, families, and communities. Youth violence is a problem in other countries in our hemisphere as well, and one area of particular concern is Central America. For the past nearly eight years, our research team has been working with partners across Central America to develop Miles de Manos (MdM; “Thousands of Hands”), a universal, multi-modal, evidence-informed and community-based youth violence prevention intervention. MdM has been widely disseminated throughout the region, and has been adopted as a key component of the national education plans of Honduras and El Salvador, despite the lack of an evidence base demonstrating its effectiveness. This project proposes a randomized controlled trial in Honduras, conducted in collaboration with the Honduran Secretary of Education and ChildFund International, experienced in-country experts in the implementation of MdM through work funded by USAID. The aims of the proposed project are: Aim 1. To examine the effectiveness of a culturally specified youth violence prevention program on improving effective parent and teacher behavior management practices and reducing both youth problem behaviors and youth association with peers and adults involved in problem behaviors. Aim 2. To investigate potential mediators of any outcomes due to the intervention, and specifically to conduct a test of the social learning theory underlying the intervention. Aim 3. To investigate potential moderators of any outcomes due to the intervention. Potential benefits of the project include filling in gaps in knowledge about community-based violence prevention programs both in Honduras and the U.S. Finding effective ways to improve the health, safety, and social cohesion of community members has the potential to benefit both countries in numerous ways, including reducing the personal and social disruptions and traumas that come from living in and leaving communities that become marked by violence.

NIH Research Projects · FY 2025 · 2020-09

The Center on Aging and Population Sciences (CAPS) at The University of Texas at Austin (UT) seeks to renew P30 Demography and Economics of Aging Center infrastructure support to continue successful programs and launch new initiatives to support population-based research on aging. CAPS’s mission is to galvanize research that illuminates how biosocial, relational, institutional, and socioeconomic forces intersect and cascade across the life course, contributing to disparities in health and aging. CAPS will advance this mission across three research themes: (1) Biosocial Processes, (2) Family and Social Engagement, and (3) Socioeconomic and Institutional Contexts. Five specific aims motivate the Center’s work: (1) foster groundbreaking population-based research on developmental processes that shape the pace and quality of aging from birth to death, (2) promote a national community of interdisciplinary population scientists who study aging, including outreach to increase the number and scope of researchers in the field, (3) cultivate and nurture the professional development of the next generation of scholars conducting population-based research on aging, (4) share data and research findings to benefit scientific and public audiences, and (5) provide the administrative infrastructure to advance the Center’s scientific mission. CAPS will support scientists from multiple academic disciplines through four Cores: An Administrative and Research Support Core, a Program Development and Pilot Core, a Communication and Dissemination Core, and an External Network Core on Sexual Orientation and Aging Populations. Continued P30 support will build on CAPS’s tremendous success. Since its launch as a new P30 Center in 2020, CAPS nearly doubled its number of affiliated faculty and expanded the number of active NIA awards to faculty by 76 percent with a 934 percent increase in funding (from $3.5M to $36.2M). The activities, visibility, and collaborative opportunities provided by P30 infrastructure funding will support CAPS faculty affiliates and expand the reach of the Center across U.S. institutions to advance the field’s understanding of the underlying biological, social, psychological, socioeconomic, and institutional contexts and processes that shape risk and resilience in aging populations.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY/ ABSTRACT Efferent feedback—a hallmark of peripheral sound coding—plays a critical role in auditory development and plasticity and offers a potential mechanism for minimizing noise-induced cochlear synaptopathy and supra-threshold perceptual deficits. However, our knowledge of how efferent mechanisms develop in humans is extremely limited. The overarching goal of this research is to understand the development of medial efferent mechanisms in humans and their involvement in auditory development. The objective of the proposed project is to systematically investigate the development of the temporal features of efferent effects. Our central hypothesis is that children exhibit developmental changes in efferent effects as a result of developmental plasticity in the brainstem. Our rationale is that detailed knowledge of how efferents work and develop will lead to a better understanding of the role of efferents in auditory development and perceptual deficits. The proposed project has two specific aims: 1) To determine the development of the efferent sensitivity to temporal fluctuations; and 2) To determine the developmental changes in the temporal dynamics of efferent effects. The proposed work is conceptually innovative because it will provide information on the poorly-understood developmental aspects of efferent effects in the children. The approach involves a compelling mix of sweep-tone OAE measurements with advanced signal processing (time- frequency analysis) techniques. The proposed research will provide significant new knowledge regarding how efferents develop in humans, and has implications for (1) for understanding the involvement of efferents in supra-threshold hearing, (2) forming theories of auditory development, (3) developing OAE-based tests of efferent function for predicting susceptibility to noise-induced hearing loss, (4) constructing accurate auditory models, and (5) designing improved hearing device algorithms. The principal investigator is experienced in conducting this kind of research in the current environment. Overall, the proposed project will make a sustained impact on our understanding of the human efferent system and its development, and on the field of pediatric audiology.