Drexel University

NIH Research Projects · FY 2025 · 2021-05

PROJECT SUMMARY/ABSTRACT Beyond the role that individual factors (e.g. age, race, gender, and socioeconomic status) play in the progression of Alzheimer's Disease and related dementias (ADRD), neighborhood factors (e.g. social and built environments) may affect cognitive health. Critically, although African American and Hispanic individuals face the highest and most disproportionate risk for ADRD, research has traditionally excluded diverse populations. Given historic and current patterning of healthy neighborhood factors by racial and socioeconomic characteristics, these features may partially explain observed disparities in ADRD risk. To date there has been no research on the role of neighborhood environments in disparities in ADRD risk. In this study, we propose to leverage and extend extensive longitudinal data from the Multi-Ethnic Study of Atherosclerosis (MESA) to address major gaps in research on neighborhoods and disparities in ADRD. We propose to undertake large-scale collection, processing, and distribution of new neighborhood data within MESA. Our main objective is to identify unique patterns of neighborhood change related to the causes of prevalence and disparities in cognitive decline and dementia. We will attain our main objective by (Aim 1) characterizing dynamic, longitudinal neighborhood social and built environment variables (survey-based and GIS-derived) relevant to cognition for residential addresses of a MESA; (Aim 2) examining associations of neighborhood environmental characteristics with cognition and clinically relevant ADRD outcomes; (Aim 3) investigate determinants of disparities in ADRD outcomes by socioeconomic position and race/ethnicity and assess the contribution of neighborhood environments. This project is poised to provide robust new evidence about pathways and links between neighborhood environments and cognitive outcomes, with important implications for built environment science, ADRD progression research, and policies to support healthy aging. Aim 1 will create the most comprehensive longitudinal neighborhood dataset on a diverse sample with detailed cognitive and ADRD outcomes for widespread dissemination to a network of researchers. Analyses in Aim 2 will contribute to developing substantive theory on the role of neighborhoods in ADRD progression and provide guidance for urban planners to design neighborhoods that support healthy aging. Aim 3 examines component contributions to racial disparities in cognition and ADRD. Through this, we expect to identify actionable, community and clinical interventions to address and remediate racial and socioeconomic inequalities derived from the unequal distribution of environmental supports for healthy aging. We expect this evidence to support and amplify efforts to reduce disparities.

NIH Research Projects · FY 2024 · 2021-05

Abstract Seventy percent of American adults are overweight or obese, presenting an unprecedented challenge to the nation’s health systems. Effective behavioral programs exist, but these programs are intensive, long-term and require highly-trained clinicians, making them prohibitively expensive and thus limiting disseminability. Approaches to decreasing costs include replacing highly-trained clinicians with paraprofessionals, reducing contact frequency, and/or automating intervention. However, although these alternative interventions result in considerably lower average weight losses, variability of weight loss is high. Specifically, and consistent with a Supportive Accountability Model, a substantial minority of participants in high-intensity interventions receive no benefit, while a subset of those receiving low-intensity interventions achieve clinically significant weight loss. An ideal weight loss treatment system would enhance outcomes and reduce costs by matching each participant to the intervention he/she needs, thus adapting to participants’ needs and conserving resources where they are not needed. Stepped care represents one such system, but has had mixed success and suffers from a number of shortcomings. The innovative artificial intelligence (AI) strategy of reinforcement learning (RL) provides rapidly and repeatedly-varying features of intervention, continuously "learning" which features provide optimal responses for which participants. Our team recently completed a pilot of an AI weight loss system in which overweight adults received a brief in-person weight loss intervention and then were randomly assigned to receive 3 months of non-optimized interventions (i.e., 12-minute phone calls) or an optimized combination of phone calls, text exchanges, and automated messages, selected based on each participants’ response to each intervention as determined by weight and behavioral data. As hypothesized, we achieved equivalent weight losses at a fraction of the time cost. The proposed study would recruit 320 overweight adults, provide 1 month of group-based behavioral weight loss treatment and then randomize participants to either continue to receive group-based behavioral weight loss in a remote format for 11 months (BWL-S) or to reinforcement learning-based treatment (BWL-AI). In line with our Supportive Accountability model, BWL-AI would vary modality, intensity and counselor skill based on continuously-monitored participant digital data. The proposed study--the first of its kind--would expand on our pilot in several ways including sample size, duration, and features of intervention selected by the AI system. Aims of this project are to test the hypotheses that weight loss outcomes in BWL-AI will be equivalent to or better than BWL-S, and that the cost per participant and per kg of lost weight will be less in BWL-AI than in BWL-S. Other include characterizing the AI system (in terms of interventions selected), assessing feasibility and acceptability of the refined AI system, evaluating psychological and demographic predictors of AI intervention selection and investigating differences between responders and non-responders in how the AI system allocates resources.

NIH Research Projects · FY 2025 · 2021-04

PROJECT SUMMARY / ABSTRACT The success of behavioral weight loss programs is undermined by weight regain. Controversy exists about how much physiological adaptations to the weight reduced state contribute to weight regain. Further, little is known about the relative contributions to relapse of increased metabolic efficiency and increased appetitive drive. Even if metabolic efficiency increases with weight loss, this does not necessarily mean that successful dieters are hypo- metabolic in their weight-reduced state. To address these scientific questions, we will recruit 100 individuals into a weight loss program based on a modified version of the Diabetes Prevention Program. Qualified participants will be assessed at baseline and reassessed if they attain a minimum 7% weight loss (called month 0) and undergo follow- up assessments 4 and 12-months later. Reassessment at month 4 will allow us to study the transition to maintenance as a dynamic process (i.e., change from month 0 to 4), not just as a discrete change of state (from baseline to month 0). Changes in physiological measures of metabolism and appetite during weight loss will be used to predict individual differences in weight regain. Physiological outcome measures will include: 1) energy metabolism (e.g., resting and non-resting energy expenditure, 2) neural indicators of appetitive drive (e.g., striatal activation to food cues and food tastes) and 3) samples will be collected for studies of neuroendocrine responses to fasting and fed states (e.g., leptin, GLP-1). A comprehensive biobank of blood, fecal, muscle and adipose tissue will also be collected for future discovery studies. Our measures and expertise will provide new insight into the physiological determinants of weight regain following weight loss that could help improve obesity treatments in the future.

NIH Research Projects · FY 2025 · 2021-04

Project Summary This application describes a 5-year plan to investigate the neural dynamics that underpin distortion in memory, integrating computational modeling approaches with functional neuroimaging (fMRI) and non-invasive brain stimulation techniques (TMS). The candidate, a cognitive neuroscientist with a background in memory consolidation and experience in fMRI and TMS methods, seeks new training in computational modeling and model-based fMRI analysis under the mentorship of Dr. Anna Schapiro and Dr. Sharon Thompson-Schill. The training will take place in the first 2 years of the proposal (Aim 1), after which the candidate will complete Aims 2 and 3 as an independent researcher. The proposed experiments aim to fill a critical gap in our understanding of memory distortions by examining them as a function of multiple sources of information: memory for the specific details of the event, supported by the hippocampus, and influence by more general prior knowledge, supported by cortical regions. A predominant model predicts that different versions of the same memory are stored in the hippocampus and cortex: a detailed version, and a general, gist-like version, respectively. However, it is unclear whether these traces coordinate or compete in supporting memory and whether such interactions are shaped by cognitive and neural constraints. The proposed experiments make use of a recently developed spatial memory task in which the locations of animals and objects are organized by their category membership. Critically, retrieval can be separated into two components: memory for the image's location (magnitude of error) and the influence of category knowledge (bias towards images from the same category). Anticipating that these two measures will be supported by the hippocampus and cortex, respectively, the candidate will investigate how their dynamic interplay gives rise to distortions by developing a neural network model with hippocampal and cortical aspects. Aim 1 addresses the hypothesis that there is naturally occurring variation in whether the hippocampus and cortex cooperate or compete in supporting episodic memories, using fMRI to test predictions made by the model. Aim 2 introduces a causal manipulation (TMS) to test whether constraints to the memory system drive the hippocampus and cortex to compete to encode new memories. Cortical disruption during encoding is predicted to boost hippocampal function, leading to more accurate memory. Aim 3 will investigate whether known consolidation mechanisms (i.e. memory replay) competitively prioritize the retention of hippocampal and cortical memory traces. A novel behavioral manipulation is developed to shift replay to prioritize either specific or general components of a memory, and this will be used assess its functional relevance. Completion of these aims will reveal novel insights into the hippocampal- cortical interactions that give rise to distortions in memory. Understanding these interactions will shed light on how their dysfunction leads to pathology and has the potential to aid clinical researchers in the development of treatments for patients suffering from subtle impairments in memory, such as stroke patients.

NIH Research Projects · FY 2025 · 2020-12

PROJECT SUMMARY Hereditary Spastic Paraplegia (HSP) is a heritable neurodegenerative disorder in which patients suffer from progressive weakness, spasticity of lower limbs and gait deficiencies. The disease mainly manifests as adult- onset die-back degeneration of the corticospinal tracts (CSTs). SPAST, also called SPG4, encodes spastin, which is an enzyme that severs microtubules. By far, SPAST is the most common gene mutated in HSP. To date, haploinsufficiency resulting from reduced functional spastin levels has been the prevalent mechanistic explanation for HSP-SPG4. However, haploinsufficiency fails to explain why there are no developmental abnormalities in HSP patients and why axonal degeneration is mostly confined to the CSTs. In addition, SPG4 knockout (KO) mice display only very mild motor deficits, with no reports of CST die-back. A new mouse model in the laboratory of the PI has been designed specifically to test gain-of-function toxicity of mutant spastin proteins as the cause of CST die-back and HSP-like motor deficits. The central hypothesis of this proposal is that the toxic properties of mutant spastin proteins are the cause of HSP-SPG4, whereas reduced functional spastin levels do not cause HSP but render axons more vulnerable to the disease-specific hit. Mechanistic hypotheses will be investigated via transgenic mouse models (including a new mouse established in the PI’s laboratory, the SPAST knockout mouse, and the mouse that is generated by crossing the two), as well as forebrain glutamatergic neuronal cultures derived from isogenic human induced pluripotent stem cell (hiPSC) lines. Catwalk gait analyses and CST anatomical assessments on the mice will be conducted to compare and contrast the phenotypes resulting from toxicity of mutant spastins with those resulting from reduced functional spastin levels. The hypothesis will be tested that crossing the two mouse lines will result in a more extreme HSP- like phenotype than displayed by either of the parent lines. Dose dependent cytotoxicity of accumulated mutated spastin proteins, a key prediction of a gain-of-function mechanism for the disease, will be evaluated. Decreased microtubule acetylation observed in the afflicted axons is posited to result from higher histone deacetylase 6 (HDAC6) activity elicited by mutant spastins and is posited to be the main cause of the die-back degeneration of CSTs. Potential mechanistic explanations for the greater HDAC6 activity will be explored. Reduced microtubule mobility resulting from reduced microtubule severing (due to less functional spastin) is posited to be the main cause of the greater vulnerability of the axon to the mutant spastins. Contemporary molecular biological, live-cell imaging, anatomical and behavioral approaches will be used to test these hypotheses. Successful resolution of these issues will lead to better prospects for treating patients with HSP-SPG4, and also provide insights into microtubule-based mechanisms that may be common across HSPs caused by mutations of other genes.

NIH Research Projects · FY 2025 · 2020-12

Spasticity is a debilitating condition which emerges in up to ~75% of individuals with spinal cord injury (SCI), with most experiencing spastic episodes one year after injury. Current pharmacological approaches to decrease spasticity (i.e. baclofen, tizanidine, botulinum toxin) lead to significant undesirable side effects such as sedation and dizziness. More importantly, they also induce a profound depression of spinal reflex excitability which significantly reduces muscle activity and impedes conventional rehabilitative efforts. There is therefore a critical need to identify alternate avenues. The last decade has seen a critical breakthrough in the SCI field with the use of stimulation-based therapies, in particular epidural stimulation, to further modulate the excitability of spinal networks and enhance functional recovery after SCI. Although promising, these treatments are invasive, costly, and require highly skilled and specialized teams. In contrast, non-invasive transcutaneous spinal cord stimulation (tSCS) has the potential to be rapidly adapted in clinical rehabilitation settings. This project is designed to advance our understanding of the neuroplasticity triggered by 6 weeks of repeated lumbar tSCS initiated acutely, to prevent the development of spasticity, or chronically, to decrease spasticity once spinal hyperexcitability has fully developed. Aim 1 will determine if tSCS contributes to decrease spasticity/hyperreflexia through restoring spinal inhibition in lumbar spinal networks. Behavioral correlates of spasticity will be monitored over time. In a terminal experiment, the effect of tSCS on spinal inhibitory pathways (homosynaptic depression, reciprocal inhibition, and presynaptic inhibition) will be correlated to the reorganization of inhibitory/excitatory inputs to motoneurons and primary afferents. Aim 2 will determine if tSCS restores motor-evoked potentials (MEPs) originating from above and below the injury after SCI. During a terminal experiment, MEPs initiated by a stimulation to the spinal cord below or above the injury will be recorded as well as synaptic transmission in the cortico-reticulospinal pathway. The modulatory effect of proprioceptive feedback on the MEPs of various origin will also be evaluated. The contribution of primary afferents (VGlut1+/paravalbumin) and descending tracts (vGi) to increased motor output and normalization of the SCI-induced facilitation of proprioceptive afferents will be evaluated. Because spastic symptoms, such as spasms and uncontrollable reflexes, render rehabilitation and activity-based therapies such as locomotor training challenging and less effective, Aim 3 will determine if decreasing spasticity with tSCS prior to the initiation of a step-training program improves locomotor recovery. Spasticity and locomotor recovery will be evaluated over time and will be correlated to the return of spinal inhibition and cortico-reticulospinal transmission. The proposed research project is consistent with the goals of the NIH/NINDS by addressing a current gap in knowledge and delineating the mechanisms of tSCS. Understanding the mechanisms underlying the beneficial effect of non-invasive interventions is critical to optimize evidence-based clinical practice and fast-track its use in the SCI community.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY / ABSTRACT Hereditary Spastic Paraplegias (HSP) are heritable neurodegenerative diseases in which progressive degeneration of corticospinal axonal tracts results in limb weakness, spasticity and gait deficiencies. These symptoms result from a dying back pattern of degeneration of corticospinal axons, which also display prominent swellings of unclear pathological significance. The commonest form of HSP, termed SPG4-HSP, is caused by mutations in the SPAST gene, which codes for a microtubule-severing protein called spastin. To date, the prevailing mechanistic hypothesis for the etiology of SPG4-HSP is haploinsufficiency, meaning that the corticospinal tracts degenerate because of insufficient functional spastin. However, several major disease features are not readily explained by this etiology, and it is not clear how reduced microtubule severing would promote corticospinal axonal degeneration. Providing novel information that may fill a major gap in our knowledge of SPG4-HSP pathogenesis, recent work of the Principal Investigators revealed toxic properties of mutant spastin proteins, suggesting that a gain-of-function mechanism operates in SPG4-HSP. Curiously, both mechanisms negatively affect fast axonal transport (FAT), a cellular process fueled by molecular motor proteins that allows bidirectional movement of vesicular cargoes along axons. Based on a strong experimental premise, it is hypothesized in this multi-PI grant proposal that abnormalities in microtubule organization associated with reduced spastin levels cause FAT deficits and axonal swellings (loss-of-function). On the other hand, toxic effects of mutant spastin protein cause different FAT deficits that are mediated by casein kinase 2 (CK2), and these deficits promote corticospinal axon degeneration (gain-of-function). The former makes the axon more vulnerable, but it is the latter that suffices for corticospinal axon degeneration. The proposed work seeks to test these hypotheses by directly comparing a mouse model with a single SPAST allele (SPAST +/-) with a transgenic mouse model with both endogenous mouse SPAST alleles intact that additionally expresses human spastin bearing a pathogenic mutation associated with SPG4-HSP (spastin-C448Y mice). In Aim 1, these models will be individually crossed with mice that selectively express eGFP in corticospinal motor neurons (CSMN), so that loss-of and gain-of-function contributions to the disease can be investigated. In Aim 2, FAT deficits will be studied in neurons cultured from these animals, and specific hypotheses for the etiology of the deficits will be tested. In Aim 3, studies are proposed using transgenic spastin-C448Y mice in which autophagy is experimentally enhanced or CK2 levels are experimentally reduced, to test the hypothesis that these manipulations will prevent or reduce corticospinal axon degeneration and associated behavioral deficits. The overall significance of this project is to establish mechanisms underlying SPG4-HSP and forge a path toward effective therapies for patients.

NIH Research Projects · FY 2024 · 2020-09

Somatosensory feedback from the limbs is essential for locomotion and its recovery after spinal cord injury. To achieve stable locomotion, the spinal cord needs to process afferent feedback signals and properly adjust muscle activation and interlimb coordination. Crossed-reflex pathways, specifically, are important for gait stability and balance, which are impaired in various motor disorders and in the elderly. Recently, significant progress has been made in decoding the organization and function of the central spinal locomotor circuitry and its brainstem command system. But the interactions of somatosensory feedback with the spinal circuitry during locomotion have yet to be understood on the same level of detail. In this project we propose to address this gap of knowledge by combing mouse genetics, in vivo electrophysiology, and behavioral analyses with computational modeling of spinal circuits and the musculoskeletal system to systematically dissect sensory afferent connectivity to the locomotor circuitry, including genetically identified neuron populations, and their function in interlimb coordination. Studying the organization of crossed reflexes and their interactions with spinal locomotor circuitry will provide critical information for rehabilitative strategies. This multidisciplinary project will be performed in close interactive collaboration between two investigators with strong and complementary expertise in computational (Simon Danner, PI) and experimental studies of neural control of locomotion (Turgay Akay, Co-PI). The project has the following three aims: (1) Delineate the involvement of multiple spinal interneurons in the processing of sensory information and interlimb coordination by studying crossed reflexes at rest and during locomotion; (2) Design a predictive computational model of the spinal locomotor circuitry and its interactions with the mouse musculoskeletal system; (3) Integrate modeling and experimentation to uncover underlying neural mechanisms. The model will be used to derive informative predictions that will then be tested experimentally. This process has the advantage of providing an explicit and consistent theoretical framework for experimentation, thereby reducing the number of necessary experiments while increasing the information gained per experiment. In summary, the proposed multidisciplinary approach is based on state-of-art experimental and modeling methods and will provide important and novel insights into the neural organization of the spinal locomotor circuitry responsible for sensorimotor integration and interlimb coordination during locomotion that cannot be obtained by experimentation or modeling alone.

NIH Research Projects · FY 2025 · 2020-09

Project Summary The mission of the 4th Annual Immune Modulation and Engineering symposium, which will be held at Drexel University on Dec. 7-9, 2022 is to bring together researchers in biomedical engineering and basic and translational immunology to advance the rapidly emerging field of immune engineering. The speakers and attendees represent leaders in this field, with expertise in collaborating across disciplines to generate innovative solutions to treat cancer, infectious disease, immunological disorders and major injuries by modulating the immune system. The major objectives of this symposium are to provide a forum for the sharing of cutting edge ideas in immunomodulation, to stimulate cross-disciplinary collaborations, to introduce the next generation of scientists to this new field, and to identify challenges and opportunities to advance new and innovative technologies. Philadelphia is a prime location to host this event, as it is a recognized hub for immune modulation and engineering, with a thriving community comprising academic, entrepreneurial, and industry partners. The variety of research within Philadelphia is a microcosm of that which exists throughout the world, and the field of immune engineering and modulation is certainly diverse – encompassing topics which span from molecular engineering to clinical translation. In order to cover this broad spectrum of research, we propose to develop a series of four concentrations within the symposium with each concentration including two sessions of keynote talks from a diverse lineup of speakers. These concentrations include: cancer immunology & cell delivery, immunoregulation of injury and disease, nanomedicine and synthetic biology, and regenerative medicine and immune tissue engineering. We are committed to hosting an annual symposium that is of the highest quality while also showcasing the diversity in our fields. In support of this goal, this year will feature the inaugural Diverse Perspectives in Immune Engineering opening reception, which will showcase and celebrate the value of diverse team in this field. The organizing committee represents diverse representation in terms of gender, ethnicity, career stage, and scientific discipline. Similarly, we have selected speakers who are current or future leaders in the field of immune engineering who are also diverse in their make-up and background. Throughout the planning stages we will continue to seek input from our colleagues who represent persons from disadvantaged backgrounds, those with disabilities, and other underrepresented groups in science, and make every attempt to recruit participants from diverse backgrounds. Finally, we will help attendees identify resources for child and family care in the vicinity of the symposium, and we will make it clear that infants are welcome at the symposium.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY Road traffic injuries are a major contributor to the burden of disease globally with nearly 1.3 million deaths globally and as many as 50 million injured annually with pedestrians and cyclists in low and middle-income countries (LMICs) among the most affected. Road infrastructure of the built environment (e.g., sidewalks), neighborhood design (e.g., street connectivity) and urban development (e.g., urban sprawl) are key determinants of the risk of pedestrian injuries. In LMICs, poor road infrastructure and neighborhood design are acknowledged as being important contributors to rising numbers of road traffic injuries and deaths, but there are few studies systematically identifying and quantifying what specific features of the built environment are contributing to motor vehicle collisions in these settings. Within LMIC cities, there are often large disparities where infrastructure is improved that reflect socioeconomic characteristics, leading to health inequities in road traffic injury. The paucity of georeferenced data on the built environment in LMICs has made research on road traffic injuries more difficult, though recent advances in computer vision and image analysis combined with Big Data of publicly available, georeferenced, images of roads worldwide (e.g., Google Street View, GSV) can help overcome the paucity of data and the cost and time limitations of collecting and analyzing data on the built environment in LMICs. Automated image analysis has largely been made possible via deep learning, a subfield of artificial intelligence and machine learning and relies on training neural networks to detect and label specific objects within images. These methods can drastically reduce the barriers to citywide built environment and traffic safety research in LMIC cities, thus substantially increasing research capacity and generalizability. My career goal is to become an independent investigator in global urban health with a focus on road safety and the built environment in LMICs. I propose undertaking research and training in deep learning methods applied to public health in the setting of Bogota, Colombia: 1) Develop neural networks to create a database of BE features of the road infrastructure from image data and to create neighborhood typologies from those features; 2) Assess the association between neighborhood-level BE features and typologies and pedestrian collisions and fatalities and road safety perceptions; 3) Assess the association of neighborhood social environment characteristics with pedestrian collision and fatalities, perceptions, and BE features and typologies. I am seeking additional training in 1) developing competency in deep learning methods applied to public health; 2) creating neighborhood indictors and typologies of health and the built environment; 3) applying Bayesian spatiotemporal models to understand how neighborhood characteristics and typologies influence health; 4) develop skills in multi-country collaboration, grant writing and overseeing research projects in LMICs.

NIH Research Projects · FY 2024 · 2020-09

PROJECT SUMMARY We here focus on determining the algorithms that enable highly similar visual information to be transformed into diverse, behaviorally relevant outputs. We also seek to determine the mechanisms that generate these algorithms. Understanding how visual information is transformed into representations relevant for behavior is key for restoring sensorimotor transformations in those who are blind or visually impaired, or suffer from sensory processing disorders. For our visual inputs, we use looming stimuli, the 2-D projections of an object approaching on a direct collision course. Looming stimuli elicit a conserved diversity in behavioral responses across species that are necessary for survival. This diversity is thought to emerge through parallel sensorimotor processing pathways that differentially transform visual features of a looming stimulus into motor outputs. Limited access to both visual feature encoding and visual feature integrating circuit components has however limited the development and biological validation of the algorithms utilized across pathways. We circumvent these limitations by using Drosophila melanogaster that provides the necessary electrophysiological and genetic access to the cell types that participate in these sensorimotor transformations. Our preliminary data suggest looming information is transformed within eight descending sensorimotor pathways (DN) that receive features of looming stimuli from up to six optic lobe columnar projection neuron (OLCPN) cell types. In this interdisciplinary grant, we capitalize on the complementary expertise of Dr. von Reyn (PI), who has pioneered electrophysiological, behavioral, and genetic methods for investigating feature integration within OLCPN and DN, and Dr. Ausborn (co-PI), who has broad expertise in the development of mechanistic biophysical circuit models for the analysis of neural computations within mammalian and invertebrate systems. Here we characterize the extent to which different DN intrinsic properties and circuit mechanisms account for the observed output diversity. In Aim 1 we combine electrophysiology, RNAi silencing, and computational modeling to establish, at a molecular level, intrinsic integration mechanisms for each DN. In Aim 2, we combine electrophysiology, optogenetics, and computational modeling to determine OLCPN synaptic inputs to DN. In Aim 3, through concurrent model and experimental probing, we evaluate the dominant mechanisms that determine looming feature integration algorithms utilized across the DN population. This project will provide a thorough understanding of general principles for transforming sensory information into higher order, behaviorally relevant representations.

NIH Research Projects · FY 2024 · 2020-08

Project Summary For a foreseeable future antimalarial drugs will remain a mainstay for the management of malaria worldwide. While the pipeline of new antimalarial compounds has begun to look promising in recent years, the specter of drug resistance is always looming. This fact demands continued efforts to discover and develop new antimalarial drugs. Among the promising new antimalarial compounds to emerge in recent years are those that disrupt Na+ homeostasis in Plasmodium falciparum. Two of these compounds (a spiroindolone and a dihydroisoquinolone) have progressed to Phase II clinical trials and have shown to be highly potent against P. falciparum and P. vivax infections with in vivo parasite clearance times that are even faster than artemisinin, the fastest acting antimalarial drug in use. Remarkably, at least 20 distinct chemical classes of compounds, comprising ~8% of all antimalarials present in the Malaria and Pathogen Boxes distributed by Medicines for Malaria Venture (MMV), also have the propensity to disrupt Na+ homeostasis in P. falciparum. Several lines of evidence support the notion that all these compounds inhibit a parasite-encoded Na+-pumping P-type ATPase named PfATP4. Thus, PfATP4 presents a highly attractive target for a very broad range of small molecules. Extraordinarily fast clearance of parasites in vivo by PfATP4-active compounds holds the promise for these compounds to emerge as potential replacement for artemisinin, something the world needs to be prepared for given the potential spread of artemisinin treatment failures. While two PfATP4-active compounds have advanced to clinical trials, the history of drug development advises prudence to explore back-up compounds to account for pipeline attrition and mitigating chances of failure against a valuable target. It is with this background that we are proposing here to conduct a medicinal chemistry campaign that would deliver additional preclinical candidates that meet the stringent criteria advocated by MMV. Over the past decade we have carried out extensive medicinal chemistry campaign to identify highly potent PfATP4-active compounds that belong to different chemical classes than the two compounds under clinical investigations. We aim to identify a pre-clinical candidate compound guided by potency, metabolic stability, physicochemical and pharmacokinetic properties, in vivo efficacy in a humanized mouse model of P. falciparum infection and safety studies. These studies will be allied with PK/PD simulations to ensure a compound that meets safety and single dose criteria. We also propose to investigate the possibility of minimizing resistance emergence by exploring the effects of targeting two different domains of PfATP4 by combination of distinct chemical scaffolds.

NIH Research Projects · FY 2024 · 2020-08

Project Summary It is well established that African Americans have higher levels of cardiometabolic risk factors than whites and are less likely to achieve hypertension and diabetes control. The neighborhood environment is a critical structural determinant of these disparities given the disproportionate exposure of African Americans to deleterious residential environments. In light of this, we propose using the JHS, a state of the art epidemiologic cohort of African Americans (n=5,306), combined with rigorously assessed neighborhood contextual factors to examine longitudinal associations between features of the physical, social, and local healthcare environment and cardiometabolic risk factor development and management over a 20-year period. Understanding the role of changing neighborhood environments in shaping cardiometabolic risk factor development and management is critical to improving causal inferences and developing appropriate policies and interventions designed to mitigate the burden of cardiometabolic risk factors in this high-risk population. Furthermore, understanding these changes in the unique context of the South, a region of the country with the highest burden of chronic disease and urban areas characterized by high proportions of African Americans, low population density, and geographically dispersed amenities, will allow us to better understand how neighborhood processes operate in this setting and better tailor ongoing prevention efforts. The primary goals of the proposed study are to: 1) compile a multilevel database of time-varying neighborhood contextual data (i.e. physical, social, and healthcare characteristics) that can be linked to the Jackson Heart Study (JHS)— a unique, state-of-the art cohort study of African Americans and 2) to examine longitudinal associations of changes in neighborhood contextual factors with HTN and DBM development and management. Aim 1 will examine longitudinal associations between time-varying physical and social neighborhood features and cardiometabolic risk factors among African American adults. Aim 2 will examine longitudinal associations between time-varying neighborhood physical and social features and HTN and DBM control. Aim 3 will examine associations between local access to primary care and cardiometabolic risk factor development and management and whether features of the physical and social environment modify associations. This project will build upon detailed neighborhood data collection from Exams 1-3, incorporate emerging neighborhood data collection techniques, and take advantage of the collaborative partnership established between the Drexel University Dornsife School of Public Health and the JHS through the Center for Integrative Approaches to Health Disparities.

NIH Research Projects · FY 2024 · 2020-08

Project Summary / Abstract The broad objective of this study is to understand the mechanism by which multiple stem cell populations are controlled by the niche to coordinate daughter cell production. Coordination between adult stem cells is essential to maintain tissue homeostasis and prevent tumorous overgrowth. Many structures, including the hair follicle, hematopoietic network and developing ovary require tight control over stem cell proliferation and coordination of daughter cell production from distinct stem cell lineages. In most cases, the molecular mechanisms orchestrating this coordination are largely unknown. Leveraging the power of Drosophila genetics and establishing a system for longitudinal (20+ hours) live imaging of stem cells within an endogenous niche we have begun to reveal the mechanisms controlling stem cell coordination in the testis. Somatic stem cells and germline stem cells (GSCs) of the testis must generate daughters in a precise 2:1 ratio for germ cells to effectively differentiate into sperm. Our live imaging has revealed a modified cytokinesis program in GSCs as the mechanism to coordinate release of one GSC daughter only after it correctly associates with two daughters of the somatic stem cell lineage. This modified cytokinesis program is controlled at two stages—a pause regulated by Jak/STAT signaling from the niche and a trigger for completion of cytokinesis derived from the somatic stem cells. Both control points must be properly executed or stem cell cytokinesis fails, stem cell tumors form and germ cells fail to differentiate. While we have identified the source of both the pause and trigger, the mechanisms by which these signals control GSC cytokinesis remain unknown. In addition, the degree to which soma and germline communicate to ensure that proper ratios of daughter cells are produced is largely unexplored. This study uses molecular genetics and extended live imaging to interrogate the specific mechanisms by which niche signals and somatic stem cells combine to regulate GSC cytokinesis to ensure coordination between stem cells in the testis niche. By establishing a method for live imaging of both stem cell populations, we can now also directly visualize stem cell coordination in real time and interrogate the cross-talk between stem cell lineages that is essential for tissue homeostasis. Successful completion of the proposed work will provide significant insight into stem cell-niche interactions and how these may become disrupted during tumorigenesis, setting the foundation for future work aimed at identifying similar mechanisms at play in other tissues and species.

NIH Research Projects · FY 2024 · 2020-07

Rising maternal mortality rates, and the significant racial/ethnic disparities that characterize them, result in black women dying from pregnancy-related causes at three to four times the rate of their white counterparts. Considering that for every maternal death, over 100 women experience severe maternal morbidity —a life- threatening diagnosis or condition occurring as a direct result of pregnancy and childbirth—the implications of reducing maternal morbidity for black maternal health are profound. Morbidity during the postpartum period, as represented by postpartum hospital readmissions, is also 30% more likely to impact black women. Effective interventions developed from a comprehensive, multilevel evidence base are needed to successfully eliminate these disparities. However, many of these multilevel factors remain understudied, and translation of evidence into action remains challenging due to complex inter-relationships across factors that produce unanticipated outcomes. The objectives of this study are to address this twofold gap by 1) investigating neighborhood opportunity access as an understudied multilevel factor in relation to racial/ethnic disparities in maternal morbidity and 2) using systems science methodologies, such as system dynamics, in a participatory framework to develop a causal system map that contextualizes the role of neighborhood opportunity access within the complex, inter-related system shaping racial/ethnic disparities in maternal morbidity. Using Philadelphia, PA as a base case, I will partner with the Maternal, Child, and Family Health Division in the Philadelphia Department of Public Health to leverage linked hospital discharge, birth record, and neighborhood indicator data to accomplish the following aims: (1) To estimate associations between neighborhood opportunity access and severe maternal morbidity, using a composite measure that includes indicators from the social, physical, and built environment, and assess whether it explains racial/ethnic disparities; (2) To estimate associations between neighborhood opportunity access and postpartum hospital readmissions, and assess whether it explains racial/ethnic disparities; (3) To develop a qualitative system map detailing the causal feedback structure driving associations between neighborhood opportunity access and racial/ethnic disparities peripartum maternal morbidity, contextualized within an ecosystem of other multilevel factors, using participatory system dynamics methodologies. The K01 will allow me to gain integral training in the use of administrative data for population health, advanced spatial statistics to geospatially contextualize health disparities, and participatory systems science methodologies to support the translation of evidence into action to eliminate health disparities. This will help me achieve my long-term goal of successfully building a rigorous research agenda that uses applied methodologies to understand the sociostructural determinants of racial/ethnic disparities in maternal and infant health and informs the development of sustainable policies and programs to eliminate them.

NIH Research Projects · FY 2024 · 2020-06

Project Summary/Abstract In 2016, 47,000 individuals who initiated dialysis in the United States (~42% of all incident dialysis patients that year) had obesity, with a body mass index (BMI) of ≥ 30 kilograms per meters squared. Across the BMI spectrum, individuals with kidney disease commonly lose weight after initiating dialysis treatment. However, whereas body weight typically stabilizes after the first several months of dialysis among patients without obesity, those with obesity often continue to lose weight. Both people with and without obesity who are on dialysis may lose weight due to muscle wasting and malnutrition, and recent studies have identified weight loss as a risk factor for death among people on dialysis, independent of BMI. Yet, some of the weight loss observed among obese dialysis patients may also reflect deliberate attempts to improve health, mobility, or access to kidney transplantation. Currently, there are no guidelines to help clinicians to differentiate between healthy and high-risk weight loss among people with obesity on dialysis. Further, typical obesity management paradigms are not easily transferrable to obese people with end-stage kidney disease, given factors such as chronic malnutrition, inflammation, and sarcopenia in this population that may modify the risks and benefits of different weight loss strategies. Therefore, the overarching goal of this five-year research proposal is to define healthy and high-risk weight loss phenotypes among people with obesity who are on dialysis, and to provide clinically feasible tools to improve obesity management in the setting of end-stage kidney disease. We will accomplish this goal by conducting three distinct but interrelated studies. In the first study, we will qualitatively determine patient-prioritized endpoints of weight loss, in addition to patient, physician and other stakeholder perspectives on the key factors that differentiate healthy from high-risk weight loss on dialysis. In the second study, we will leverage a national dataset of 23,000 obese dialysis patients and apply constructs of high and low physiologic reserve to derive healthy and high-risk weight loss phenotypes. We will then develop a weight- loss risk calculator tool that predicts the risks of hospitalization and death that are associated with each weight loss phenotype, using dynamic predictive joint models and machine learning techniques. In the third study, we will enroll 250 obese dialysis patients in a prospective, longitudinal study across five regions in the United States to evaluate the association between nutritional, inflammatory, and hemodynamic biomarkers and measures of health trajectory that are not typically captured in registry data, such as sarcopenia, dynapenia, body composition, and patient-prioritized endpoints such as quality of life. In accomplishing its aims, this research will provide urgently needed knowledge and tools that will improve the medical management of tens of thousands of people with end-stage kidney disease and obesity, ensuring that clinicians will be better able to incorporate patient-prioritized outcomes into assessments of weight loss interventions, and recognize and mitigate the effects of high-risk weight loss.

NIH Research Projects · FY 2024 · 2020-04

Almost 2.5 million people visit the emergency room each year in the United States as a consequence of sustaining a traumatic brain injury (TBI). Of these almost 75% are diagnosed with a mild TBI or a concussion, and almost a third of these patients go on to develop long-term behavioral problems. Executive function deficits, emotional disturbances such as depression and anxiety, affective disorders and substance use disorders are some of more common complaints of mild TBI patients. Adolescent boys and girls (high school and college-age) are more severely affected by concussions compared to older (adult) patients. Emerging data also suggest that girls and women are twice as likely to sustain a mild TBI, have different and more severe symptoms and take longer to recover from than their male counterparts. We have developed a model of mild TBI in the adolescent (5-week-old) rat and have demonstrated that despite similar extents of axonal injury in the early post-traumatic period only the female rats exhibit cognitive deficits. Importantly, as these animals age into adulthood, they begin to develop depression-like behavior, which manifests only in the estrus phase of the estrous cycle. This phenomenon of transient helplessness and anhedonia are hallmarks of premenstrual dysphoric disorder that some women experience. Our preliminary data demonstrate that activating the mesocorticolimbic dopamine circuit using chemogenetic approaches or agonist of the D2 receptor reversed the depressive-like behavior observed in injured animals. The activity of the D2 receptor varies with phases of the estrous cycle with the lowest activity occurring immediately after the hormone surge that occurs during proestrus. Blocking this surge using estrogen and progesterone receptor antagonists was able to reduce depressive-like behavior. The working hypothesis of this proposal is that mild TBI in the adolescent female rat results in the development of a hypodopaminergic state characterized by a decrease in the activity of the dopamine neurons in the ventral tegmental area (VTA) and the expression of D2 receptors in the medial prefrontal cortex (PFC). The specific aims are designed to test whether the estrogen receptor β isotype is the key mediator of the decrease in D2 receptor expression (Aim 1), whether the activation of D2 receptors within the medial PFC facilitate the reversal of the depressive-like behavior (Aim 2), and whether the activation of the DA neurons in the VTA projecting to the medial PFC will reverse depressive-like behavior. Hormone receptor antagonists will be systemically administered, D2 receptor agonist and retroAAV2 will be infused directly into the medial PFC, and Gq-designer receptors exclusively activated by designer drugs will be expressed in the VTA using an AAV vector. The data from these experiments will provide the mechanistic basis for sex-specific behavioral deficits following mild TBI sustained in adolescence.

NIH Research Projects · FY 2024 · 2019-09

Despite the long-standing literature that has demonstrated changes in driving capacity following brain injury (BI) – little is known about the relationship of these differences and increased risk for driver error or the prediction of long term driving outcome after BI. However, it is well-established that the loss of the driving privilege negatively impacts functional re-integration, mood and quality of life – resulting from the reduced ability to participate in various life activities, work and educational experiences. The challenge to increasing our understanding of how to best assess and predict driving performance after BI is two-fold. First, there is a need for novel assessment methodologies that can provide objective, detailed and repeatable metrics of driving performance. The current clinical gold standard – the behind the wheel (BTW) driving assessment, is over-dependent on subjective observations, lacks standardization, assesses only basic driving skills (due to safety limitation) and generates gross measures of performance (i.e., Pass/Fail). Second, there is a lack of follow-up studies that examine actual return to driving behaviors among individuals with BI. While some evidence for greater risk of crash involvement (often dichotomized as Yes/No) has been reported, these studies have relied heavily on self-reported data and offer little to no data about driver behaviors and/or modifications, risk-involvement, crash causing-behaviors or driving patterns. The proposed study aims to address these limitations and employs an established virtual reality driving simulator (VRDS) that outputs novel driving performance metrics that are currently not available thru clinical methodology. The VRDS generates detailed metrics that can differentiate between clinical populations. Specifically, the study will integrate VRDS into an existing clinical driving assessment program and evaluate 100 individuals with BI across the process of returning to drive (e.g., from assessment to follow- up) and a sample of healthy controls. All participants will be assessed with both current clinical protocols and VRDS. This will be followed by a 24 month follow-up study including an innovative, 3-platform approach (in- car video-monitoring, web-based self-report and driving records) to quantifying returned to driving behaviors. The data collected will be used to apply both traditional (Regression Models) and novel (Machine-Leaning Models) analytical techniques to generate predictive models of relevant outcome variables (i.e., risk involvement, crash-relevant errors) that can be used to inform tailored driver interventions and retraining.

NIH Research Projects · FY 2025 · 2018-07

ABSTRACT Severe spinal cord injury (SCI) often spares spinal circuitries innervating the hindlimbs but results in the loss of motor control below the injury due to compromised descending innervation of the cord. Plasticity after injury leads to the development of hyperreflexia and spasticity over time. Although hyperreflexia can be beneficial initially, facilitating motor output and locomotor function, it disrupts functional gains in the longer-term. The sensory afferents and their transmission within the cord are thought to be a primary mechanistic contributor to both regained locomotor function and hyperreflexia following SCI. Thus, identification of the mechanistic balance point between afferent input promoting locomotion and contributing to pathology, including hyperreflexia, after SCI is crucial to maximizing functional recovery. During the prior funding period, we demonstrated that viral delivery of brain derived neurotrophic factor (AAV-BDNF) below the lesion dramatically improves weight- supported stepping in subsets of rats and mice with complete thoracic spinal cord injury but hyperreflexia interferes with functional gains in other subsets over time. This provides a powerful experimental model where the same treatment strategy leads to beneficial and detrimental outcomes. In this renewal application, we will test the overarching hypothesis that spatial variations in plasticity and excitability across the cord due to viral BDNF contribute to functional variation in both locomotor patterns and expression of pathological reflexes. Experiments will be performed in two highly complementary neurophysiology labs with expertise in chronic recordings and rehabilitation in rats and intracellular and genetics techniques in mice. To obtain precisely controlled effects in spinal circuitry in both rodent models, we use complete SCI, eliminating descending control driven effects below the lesion, and focusing on spinal and afferent driven plasticity. The complete SCI will provide clean and unambiguous data which can subsequently guide other therapeutic work in more directly clinically translatable animal models. Using mouse and rat data together, we will determine the structural, synaptic, circuit, and synergy-related plasticity associated with the recovery of stepping, and interfering hyperflexion and hyperextension, after complete SCI. Further, the critical windows and critical neural elements supporting both locomotor improvements and the development of pathological reflexes will be determined. The establishment of the structural, synaptic, and circuit differences underlying functional locomotor gains, hyperflexion, and hyperextension will greatly contribute to mechanistic understanding of both function and pathology, and has the potential to reveal testable structural or electrophysiological biomarkers for specific pathologies. Additionally, the determination of timing, critical neuronal elements, and the mechanistic interactions of these circuits with both AAV-BDNF driven plasticity and with epidural stimulation will together reveal key therapeutic targets and potential neuromodulation-based treatment strategies to enhance locomotor function.

NIH Research Projects · FY 2025 · 2017-09

PROJECT SUMMARY Spinal cord injury (SCI) impairs sensory transmission and leads to chronic, debilitating neuropathic pain. Chronic pain afflicts over 100 million Americans and creates an enormous burden on US health care systems, costing over half a trillion dollars annually according to a recent report from the Institute of Medicine. While our understanding of the molecular basis underlying the development of chronic pain has improved, the available therapeutics provide limited relief. While our lab and others have shown that early post-SCI rehab can prevent pain development, early rehab in human SCI may not be possible due to the multisystem, polytraumatic injuries individuals with SCI sustain. Thus, there is a critical need for an adjuvant therapy to aid those individuals who are unable to participate in early rehab. Neuropathic pain is increasingly recognized as a neuroimmune disorder. While macrophages are regarded as key regulators of chronic pain development, it is unclear whether they are acting in an inflammatory or reparative manner. This R01 seeks to better understand how or if the activation state of macrophages influences nociceptive neuron excitability and pain development after SCI. We will utilize an established spinal cord injury model of neuropathic pain development and drive macrophage activation state by post-injury rehab, intrathecal administration of exosomes derived from Raw 264.7 macrophages stimulated in vitro or a phosphodiesterase 4 inhibitor by a polymer nanodelivery system that specifically targets macrophages. This proposal seeks to understand the role of macrophages that infiltrate the dorsal root ganglia and persist there chronically after SCI both in the development and maintenance of chronic neuropathic pain.

NIH Research Projects · FY 2025 · 2017-08

ABSTRACT Alzheimer’s disease (AD) is a debilitating progressive neurodegenerative disorder (ND) hallmarked by initial mild cognitive impairment (MCI) followed by dementia. The severity of AD progression is dependent upon the complex interplay between genetics, age, and environmental factors orchestrated in large part, by epigenetic histone acetylation (HA) mediated gene regulatory mechanisms. HA homoeostasis in the brain is maintained by antagonizing histone acetyltransferase (HAT) and histone deacetyltransferase (HDAC) enzymes that generate and erase cognition-linked histone acetylation marks, respectively. Reduced HA levels in the brain cause chromatin packaging alterations in neurons, with concomitant transcriptional dysregulation that is a key initial step in AD etiology. Nevertheless, the specific HATs that generate these distinct neuroepigenomic acetylation signatures in the brain, and thus serve as causative agents underlying memory impairing HA alterations in AD, remain largely unknown. Our laboratory has a long-standing interest in the HAT Tip60 as an epigenetic mediator of neural transcriptional regulatory responses in cognition and AD. We generated a robust APP;Tip60 Drosophila model system that enables us to modulate Tip60 HAT levels in neural circuits of choice under AD amyloid precursor protein (APP) neurodegenerative conditions, in vivo. Its use led to a compendium of published studies that establish a central role for Tip60 HAT mediated chromatin dynamics in cognitive function and neuroprotection in AD. During this funding period, we also made several separate and striking discoveries regarding alternative novel cellular mechanisms for Tip60 in mediating neuronal gene control that are disrupted in AD. These include: (1) experience-dependent (ED) Tip60 nucleocytoplasmic transport (NCT) and (2) a novel RNA-binding function for Tip60. The overarching goal of this proposal is to elucidate these new Tip60 functions, as well as generate novel Tip60 specific therapeutic compounds, to deepen our understanding of Tip60’s unique roles in nervous system biology and AD neuroprotection. To achieve this research goal, our team combines expertise in the unique but complementing areas of Tip60 function in cognition and AD (Elefant, PI), neuroepigenetics in RNA splicing (Heller, CoI) and novel drug discovery (Kortegare, CoI) to propose the following specific aims: In Aim 1 we functionally assess Tip60 nucleocytoplasmic transport (NCT) in neuronal experience- dependent gene control. In Aim 2 we dissect a novel bi-level neuronal function for Tip60 at the chromatin and RNA splicing level in †he brain. In Aim 3 we will generate novel Tip60 based therapeutic compounds to identify cognitive benefits of pharmacologically enhancing human Tip60’s HAT activity. Successful completion of this project will uncover novel molecular pathways, targets and early biomarkers to treat AD and generate a specific Tip60 HAT activator compound with AD neuroprotection capabilities.

NIH Research Projects · FY 2026 · 2017-05

Project Summary In recent years, several chemically diverse compounds have been identified that target PfATP4, a P-type ATPase involved in maintaining Na+ homeostasis in malaria parasites. Some of these compounds have advanced to clinical trials. Thus, PfATP4-active compounds are among the most attractive new antimalarials being developed to counter the continuing threat of drug resistance. Over the previous funding period, we have discovered some dramatic alterations in parasite physiology that accompany a short 2 h exposure to PfATP4 inhibitors. These include: i) Rapid alterations in lipid homeostasis within the parasites with reversible accumulation of cholesterol in the parasite plasma membrane (PPM); ii) Morphological changes resembling premature schizogony; and iii) Massive dephosphorylation of parasite proteins that may underlie the metabolic slowdown that follows PfATP4 inhibition. These observations reveal a collection of hitherto unknown interrelated molecular pathways, disruptions of which result in parasite demise. We found that PfATP4 inhibition appears to result in inhibition of PfNCR1, another druggable transporter, that is involved in maintaining lipid/cholesterol homeostasis within the PPM. Reduction of cholesterol content of the RBC plasma membrane results in dramatic expulsion of trophozoites from the host cell without the lysis of the RBC membrane. Remarkably, treatment with either PfATP4 or PfNCR1 inhibitors prevents this expulsion. These studies suggest an active transport of cholesterol between the RBC plasma membrane and the parasite. We found that trophozoite stage parasites exposed to PfATP4 inhibitors for just 2 h undergo massive morphological changes that resemble premature onset of schizogony events including the formation of inner membrane complexes, rhoptry-like structures and karyokinesis. In addition, trophozoites undergo massive reduction of a large number of metabolites suggestive of metabolic shutdown. We hypothesize that underlying all these events is a signaling cascade unleashed by the influx of Na+ into parasite cytoplasm following PfATP4 inhibition. In support of this proposition, we found dephosphorylation of a large number of proteins, prominent among which were molecules involved in DNA metabolism, chromosome segregation and cell cycle processes. The complexity of events triggered by PfATP4 inhibition requires a multidisciplinary approach. For this purpose, we have recruited outstanding co-investigators in consortium arrangements for the next funding period. Together, we propose to carry out the following specific aims: i) Investigate the relationship between cholesterol dynamics and its role in fatty acid and lipid transport in P. falciparum; ii) Explore the significance of dephosphorylation of proteins that follows PfATP4 inhibition; iii) Examine the causes of metabolic slowdown following PfATP4 inhibition; iv) Derive structural information for PfATP4 and PfNCR1 to understand molecular details about these validated antimalarial drug targets.

NIH Research Projects · FY 2025 · 2017-04

PROJECT SUMMARY There is a fundamental gap in our understanding of the circuit mechanisms underlying even simple naturalistic behaviors, such as making a cup of coffee, which proceed through a sequential execution of sub-behaviors. The continued existence of this gap represents an important problem because obtaining a circuit-level understanding of complex multi-step behaviors is a necessary step toward unlocking the mysteries of healthy brain function and disorders. The overarching goal is to obtain a circuit-level understanding of such naturalistic behavior. The research objective here is to unravel the logic of sensorimotor transformation in the context of odor modulation of locomotion in Drosophila. Our group has pioneered methods to quantitatively assess how odors affect a fly's locomotion. We have also described the overall transformation between the activity of the olfactory receptor neurons (ORNs) and the resulting change in locomotion and found that this transformation is well-described by a mapping between the activity in the ORN and changes in locomotor parameters. This mapping is distinct for different locomotor parameters and suggests that there are parallel sensorimotor modules. The central hypothesis underlying the research proposed here is that the third-order olfactory neurons in the fly's lateral horn (LH) play an important role in mediating this transformation. LH receives input from the fly's olfactory system and is connected to premotor neurons in the fly's brain, and is, therefore, in the correct anatomical location to transform activity in the olfactory system into changes in locomotion. In particular, we hypothesize that lateral horn output neurons (LHONs) will mediate the specific transformation between ORN activation and each locomotion parameter. This hypothesis was formulated based on previous work and preliminary data. The rationale for the proposed research is that understanding odor-guided locomotion—a complex, flexible behavior—in the context of a genetically tractable system will allow a precise delineation of the steps that underlie sensorimotor transformation in the context of naturalistic behavior. The hypothesis above will be tested by characterizing the circuit basis of modulation of locomotion by food odors using a combination of techniques, including imaging, electrophysiology, quantitative behavior, and computation. The proposed research has three specific aims. 1) To investigate the rules of olfactory sensory integration in the context of naturalistic behaviors 2) To investigate the relationship between activity in LHONs and locomotion. 3) To investigate the contribution of LHONs in different contexts. The research is innovative because it employs sophisticated statistical tools and cutting-edge experimental tools in the context of a genetically tractable model organism to obtain insights into naturalistic behaviors. The proposed research is significant because it will vertically advance our understanding of sensorimotor processes involved in naturalistic behaviors. Besides representing a vertical advance in our understanding of naturalistic behavior, another possible positive outcome of this study is a better diagnosis of neurological conditioning that occurs through improper sequencing of actions.

NIH Research Projects · FY 2025 · 2016-09

Autism spectrum disorder (ASD) is one of the most common neurodevelopmental disorders diagnosed in childhood, with a prevalence of 2% or higher. ASD presents along a spectrum, and characterization according to quantitative measures demonstrates continuous distribution of core traits extending into the general population. While both ASD diagnosis and ASD-related traits have been shown to be highly heritable, evidence also supports contributions of environmental risk factors, including prenatal exposure to air pollution and intake of certain nutrients. In order to address prior gaps in the understanding of environmental risk factors for autism, our team developed the Autism Spectrum Disorder Enriched Risk (ASD-ER) “cohort of cohorts.” In the first phase of ECHO, our cohort contributed to harmonization efforts of diet, air pollution, and neurodevelopment, and advanced use of abbreviated measures of the ASD-related phenotype, while capitalizing on the unique data for autism research presented by ECHO. Here, we propose to build off of these efforts while continuing follow-up of ASD-ER ECHO Phase-1 children through the critical and under-studied period of adolescence and early adulthood in the Trajectories and Environments in Autism: a Multi-cohort Study (TEAMS) project. The goals of this project are to: 1) Examine joint effects of early life air pollution exposure and diet on neurodevelopmental outcomes in ECHO-wide data, addressing the role that folate, fish/fatty acids, and other dietary factors may play in mitigating air pollution associations across neurodevelopmental diagnoses and their related quantitative traits (ASD, ID, and ADHD); 2) Evaluate multi-domain health trajectories of adolescents across neurodevelopmental outcomes in ECHO-wide data, and identify predictors of positive trajectories and outcomes. Using the unique longitudinal data collected through ECHO efforts, we will examine trajectories across mental and physical health and examine how these differ across neurodevelopmental diagnoses and traits. We will also seek to further characterize our specialized outcome area of neurodevelopment, and autism specifically, by conducting psychometric analyses of dimensional measures. Finally, we will 3) Maximize recruitment and retention of our cohort participants via implementation of the ECHO protocol. We will implement a unified recruitment and retention strategy facilitated by incentives and a network of support for adolescents with neurodevelopmental conditions, transition-age autistic youth, and their families. TEAMS will be the first longitudinal study of autistic younger sibling children followed from the womb to adulthood. In doing so, our project presents unique opportunities to advance understanding of environmental predictors and modifiers, conduct cross-outcome comparisons of neurodevelopmental disorders and their latent traits, characterize multi-domain trajectories and identify predictors of positive outcomes in autistic adolescents, and implement the ECHO Phase 2 protocol to ensure an expanded set of research possibilities in this important population, and ultimately, optimize outcomes for autistic individuals and their families.

NIH Research Projects · FY 2024 · 2016-09

Autism spectrum disorder (ASD) is one of the most common neurodevelopmental disorders diagnosed in childhood, with a prevalence of 2% or higher. ASD presents along a spectrum, and characterization according to quantitative measures demonstrates continuous distribution of core traits extending into the general population. While both ASD diagnosis and ASD-related traits have been shown to be highly heritable, evidence also supports contributions of environmental risk factors, including prenatal exposure to air pollution and intake of certain nutrients. In order to address prior gaps in the understanding of environmental risk factors for autism, our team developed the Autism Spectrum Disorder Enriched Risk (ASD-ER) “cohort of cohorts.” In the first phase of ECHO, our cohort contributed to harmonization efforts of diet, air pollution, and neurodevelopment, and advanced use of abbreviated measures of the ASD-related phenotype, while capitalizing on the unique data for autism research presented by ECHO. Here, we propose to build off of these efforts while continuing follow-up of ASD-ER ECHO Phase-1 children through the critical and under-studied period of adolescence and early adulthood in the Trajectories and Environments in Autism: a Multi-cohort Study (TEAMS) project. The goals of this project are to: 1) Examine joint effects of early life air pollution exposure and diet on neurodevelopmental outcomes in ECHO-wide data, addressing the role that folate, fish/fatty acids, and other dietary factors may play in mitigating air pollution associations across neurodevelopmental diagnoses and their related quantitative traits (ASD, ID, and ADHD); 2) Evaluate multi-domain health trajectories of adolescents across neurodevelopmental outcomes in ECHO-wide data, and identify predictors of positive trajectories and outcomes. Using the unique longitudinal data collected through ECHO efforts, we will examine trajectories across mental and physical health and examine how these differ across neurodevelopmental diagnoses and traits. We will also seek to further characterize our specialized outcome area of neurodevelopment, and autism specifically, by conducting psychometric analyses of dimensional measures. Finally, we will 3) Maximize recruitment and retention of our cohort participants via implementation of the ECHO protocol. We will implement a unified recruitment and retention strategy facilitated by incentives and a network of support for adolescents with neurodevelopmental conditions, transition-age autistic youth, and their families. TEAMS will be the first longitudinal study of autistic younger sibling children followed from the womb to adulthood. In doing so, our project presents unique opportunities to advance understanding of environmental predictors and modifiers, conduct cross-outcome comparisons of neurodevelopmental disorders and their latent traits, characterize multi-domain trajectories and identify predictors of positive outcomes in autistic adolescents, and implement the ECHO Phase 2 protocol to ensure an expanded set of research possibilities in this important population, and ultimately, optimize outcomes for autistic individuals and their families.