Yi Zuo - US grants

DESCRIPTION (provided by applicant): Medical innovations have significantly prolonged the human lifespan during the last century. However, there is still no way to slow brain aging or treat aging-related neuropathologies. Glia outnumber neurons in our nervous system and glia-neuron interactions are essential for synapse formation and stability. It is known that structural alteration and functional decline occur at synapses in both normal aging and neurodegenerative brains (e.g., Alzheimer s and Parkinson s diseases). However, so far there is little known about the dynamism of this synaptic change or the role, if any, glia play. The best way to study synapse/glia changes during aging is to follow the same synapse/glia over time in a living animal. At present, such in vivo studies cannot be easily achieved in the brain, because of the variability of neuron/glia types in the brain and the small size of its synapses. The vertebrate neuromuscular junction (NMJ) is the simplest synapse in the nervous system. Historically, it has contributed greatly to our understanding of synaptic organization and plasticity. The proposed research plan will exploit the mouse NMJ as a model system to examine the structural plasticity of the synapse and associated glia (also called terminal Schwann cells, or TSCs) during aging. The proposed studies combine the in vivo imaging technique with molecular examination and EM reconstruction to elucidate the role of glia in synapse remodeling during aging. The proposal has three specific aims. Aim 1 examines progressive myelination of Schwann cells in aging and attempts to answer whether such glial changes induce synapse disruption at the axon entry site and affect synapse remodeling in the whole NMJ. Aim 2 examines the molecular mechanism underlying aging-related synapse loss, and tests whether changes in laminin-TSC interactions lead to invasion of TSCs between muscle fibers and nerve terminals, and whether this leads to removal of synapses during aging. Finally, Aim 3 is designed to determine if reactive TSCs extend processes from remodeling NMJs and guide axon sprouting and reorganization of synaptic connections. Results from the proposed studies will provide important mechanistic insights into the role of glia in aging-related synapse loss, and identify glia as a therapeutic target to ameliorate synaptic pathologies associated with aging. PUBLIC HEALTH RELEVANCE This project will help to determine the role of glial cells in synaptic changes that occur during aging at the neuromuscular junction. These proposed studies utilize novel methods that allow the investigator to follow structural changes of glia and synapses in living mice, which will provide critical information about how this dynamic process affects normal aging. More importantly, the data may be used to create therapies that target glia for the treatment of neurodegenerative diseases that are characterized by synapse loss, such as Parkinson's Disease and Alzheimer's Disease, or to slow the more debilitating symptoms of normal aging.

DESCRIPTION (provided by applicant): Fragile X Syndrome (FXS) is the most frequent form of inherited mental retardation, and characterized by an abundance of immature postsynaptic dendritic spines in adult cortical neurons. The objective of this project is to examine spine dynamics and morphology in different cortical regions and layers of the brain during disease progression in a mouse model of FXS (Fmr1 KO), and to explore potential therapeutic strategies targeting different signaling pathways and cell types to correct both synaptic structural and learning behavioral defects. Using transcranial two-photon microscopy, in combination with molecular approaches to manipulate gene expression in individual cortical neurons in vivo, we propose 3 aims. Aim 1 systematically examines altered dendritic spine morphology and dynamics in the cortex of developing and adult Fmr1 KO mice. It will directly test the current hypothesis that FXS results from a developmental defect in spine pruning and maturation. Aim 2 correlates the progression of learning disability with the development of spine abnormality. It also dissects and compares the effect of two potential therapeutic strategies for FXS on synaptic structural/function and learning behavior. Aim 3 investigates neuronal and glial roles in abnormal development of the dendritic spine of cortical neurons in Fmr1 KOs. Results from the proposed studies will provide much needed details about spine dynamism during the pathogenesis of FXS in mice. Such information will help to elucidate the cellular mechanisms for this disease and potentially lead to identification of new cellular targets for treatment.

Abstract

#1236596
Zuo, Yi

This NSF award by the Environmental Health and Safety of Nanotechnology program supports work by Professor Yi Zuo to study the interaction mechanism between nanomaterials and pulmonary surfactant. Pulmonary surfactant is a detergent-like phospholipid-protein mixture that covers the entire internal surface of the respiratory tract. It plays an important role in surface tension reduction and host defense. Inhaled nanomaterials must first interact with this surfactant film before contacting lung cells and translocating to other organs. Therefore, interactions between nanomaterials and pulmonary surfactant represent the initial bio-nano interaction in the lungs. However, the interaction mechanism is still largely unknown. The research goal of this proposal is to study biophysicochemical interactions between natural pulmonary surfactants and engineered nanomaterials, thus characterizing the potential adverse health effect of inhaled nanomaterials on the respiratory system. This work is important to the general public because it will provide new data that complement the current nanotoxicological knowledge obtained from cell culture and animal-models, thus advancing current understanding of nanosafety.

Intellectual Merit:For the first time, the project team will systematically study biophysical and biochemical interactions between different nanomaterials (including carbon nanotubes, graphene nanoplatelets, and metal oxide nanoparticles) and pulmonary surfactants. This research will provide a novel insight into the interaction potential between surfactant phospholipids/proteins and carbon-based nanomaterials with unique aspect ratios/shapes. In addition, the project team will develop a novel in vitro model that mimics bio-nano interactions in the lungs, for studying the environmental, health and safety (EHS) impacts of airborne nanomaterials.

Broader Impacts: The interaction mechanism between nanomaterials and pulmonary surfactants has a translational value for nanomedicine-based pulmonary drug delivery and for pathophysiological study of respiratory diseases related to air pollution and particulate matters. Given the unique location of the University of Hawaii, the proposed work will promote participation of Native Hawaiians, Pacific Islanders, and students from other underrepresented groups. The PI will develop new undergraduate and graduate engineering curricula with interdisciplinary components, and help enhance the infrastructure for research and education. With local and international collaborations, the PI will disseminate the research to increase public awareness of nanotechnology and its potential EHS impacts.

DESCRIPTION (provided by applicant): Medical innovations have significantly prolonged the human lifespan during the last century. However, there is still no way to slow brain aging or treat aging-related neuropathologies. Glia outnumber neurons in our nervous system and glia-neuron interactions are essential for synapse formation and stability. It is known that structural alteration and functional decline occur at synapses in both normal aging and neurodegenerative brains (e.g., Alzheimer s and Parkinson s diseases). However, so far there is little known about the dynamism of this synaptic change or the role, if any, glia play. The best way to study synapse/glia changes during aging is to follow the same synapse/glia over time in a living animal. At present, such in vivo studies cannot be easily achieved in the brain, because of the variability of neuron/glia types in the brain and the small size of its synapses. The vertebrate neuromuscular junction (NMJ) is the simplest synapse in the nervous system. Historically, it has contributed greatly to our understanding of synaptic organization and plasticity. The proposed research plan will exploit the mouse NMJ as a model system to examine the structural plasticity of the synapse and associated glia (also called terminal Schwann cells, or TSCs) during aging. The proposed studies combine the in vivo imaging technique with molecular examination and EM reconstruction to elucidate the role of glia in synapse remodeling during aging. The proposal has three specific aims. Aim 1 examines progressive myelination of Schwann cells in aging and attempts to answer whether such glial changes induce synapse disruption at the axon entry site and affect synapse remodeling in the whole NMJ. Aim 2 examines the molecular mechanism underlying aging-related synapse loss, and tests whether changes in laminin-TSC interactions lead to invasion of TSCs between muscle fibers and nerve terminals, and whether this leads to removal of synapses during aging. Finally, Aim 3 is designed to determine if reactive TSCs extend processes from remodeling NMJs and guide axon sprouting and reorganization of synaptic connections. Results from the proposed studies will provide important mechanistic insights into the role of glia in aging-related synapse loss, and identify glia as a therapeutic target to ameliorate synaptic pathologies associated with aging. PUBLIC HEALTH RELEVANCE This project will help to determine the role of glial cells in synaptic changes that occur during aging at the neuromuscular junction. These proposed studies utilize novel methods that allow the investigator to follow structural changes of glia and synapses in living mice, which will provide critical information about how this dynamic process affects normal aging. More importantly, the data may be used to create therapies that target glia for the treatment of neurodegenerative diseases that are characterized by synapse loss, such as Parkinson's Disease and Alzheimer's Disease, or to slow the more debilitating symptoms of normal aging.

DESCRIPTION (provided by applicant): Timing is likely to be critical in attempts to promote restorative brain plasticity after stroke. Animal studies of stroke have revealed that ischemic injury triggers cascades of growth promoting and inhibiting cellular reactions and prolonged periods of neuroanatomical reorganization. Many ischemia-triggered remodeling events are activity-dependent and sensitive to behavioral manipulations. There is a growing awareness that rehabilitation strategies might capitalize on this sensitivity to optimize stroke outcome, and that this is likely to require that interventions be timed to coincide with more dynamic stages of remodeling, a timing likely to vary with stroke and patient characteristics, including age. However, the specific cellular events underlying time- dependencies in post-stroke rehabilitation continue to be poorly understood, making it impossible to clearly target them to optimize and tailor rehabilitation strategies. This project is focused on understanding how behavioral experiences differentially impact, depending on timing, post-ischemic neural and vascular remodeling events and their coordination, and the relevance of these time-dependencies for long-term outcome. This will be studied in a mouse model of chronic upper extremity (forelimb) impairments resulting from unilateral ischemic motor cortical damage in which functional impairments are improved by motor rehabilitative training of the paretic limb or exacerbated by compensatory skill learning with the nonparetic limb. Repeated in vivo imaging of synaptic elements, vascular microstructure and blood flow will be used together with sensitive behavioral measures, high resolution mapping of motor cortical organization and quantitative light and electron microscopy to reveal time- and age-dependencies in the effects of functionally beneficial and detrimental experiences on neural and vascular remodeling in peri-infarct cortex, and the consequences of these effects for cortical reorganization and behavioral outcome. The central hypothesis of this project is that behavioral experience- and injury-induced neural and vascular plasticity interact in a time- and age-dependent manner to remodel neural connections and vasculature in remaining motor cortex and to influence behavioral outcome. The specific aims are to test the hypotheses that motor rehabilitative training (1) interacts with post-ischemic neural and vascular plasticity to promote functionally beneficial remodeling of peri-infarct cortex but that this interaction is dependent upon (2) angiogenesis, (3) on its specific timing and duration relative to the onset of ischemic injury, (4) on its timing relative to the development of compensatory skill learning with the nonparetic limb and (5) on the age during which ischemic damage is incurred. The long-term goal of this project is to identify neural and vascular events that create time-dependencies in motor rehabilitative training efficacy so that these events can be targeted to tailor and facilitate the effects of rehabilitative training and to improve long-ter outcome after stroke. PUBLIC HEALTH RELEVANCE: Rehabilitative training approaches remain the primary means of improving function in the chronic period after stroke, but they are far from perfect and there i insufficiently detailed knowledge of their mechanisms to understand what needs to be changed to improve them. This project will reveal neural and vascular events that underlie time- and age-dependencies in motor rehabilitative training effects after stroke. The results will improve our understanding of the brain changes underlying rehabilitation efficacy and reveal new targets for optimizing and tailoring treatments for post-stroke disabilities.

Abstract
PI Yi Zuo
1254795

Pulmonary surfactant (PS) plays a crucial role in maintaining the normal respiratory mechanics by reducing the alveolar surface tension to near-zero. The research goal of this proposal is to study the biophysical mechanisms of PS and PS-drug interactions, using combined experimental and computational methods. There are 2 objectives: Objective 1. Study of biophysical mechanisms of natural pulmonary surfactant. Objective 2. Study of interactions between natural pulmonary surfactant and therapeutic agents (corticosteroids).
The proposed studies include combinations of state-of-the-art methods that are being used in novel ways to gain a complete understanding of the mechanisms involved.

This work is important to the general public because it will provide new insight into the role that PS plays in health and disease, thus advancing neonatal care in the United States. The primary educational goal of this proposal is to improve participation and success of Native Hawaiians, Pacific Islanders, and students from other underrepresented groups. The PI will also collaborate with the March of Dimes Foundation Hawaii Chapter to disseminate basic knowledge of prevention and management of preterm birth to Hawaiian youth.

DESCRIPTION (provided by applicant): Synapses are the sites of information processing in the mammalian brain. While generation and persistence of synapses during learning make them potential substrate for circuit modification and memory storage, the molecular mechanisms underlying synaptic structural changes and synapse diversity remain to be elucidated. Dendritic spines are the postsynaptic sites for the majority of excitatory synapses in the brain. Using an innovative combination of in vivo two-photon imaging and retrospective Array Tomography, the goals of this proposal are to determine the molecular composition and local connectivity of learning-related synapses, and to reveal principles of circuit remodeling during learning. We propose three specific aims. Aim 1 examines the protein expression of individual spines (postsynaptic structures of excitatory synapses) during the process of synaptogenesis. Such expression patterns will be compared with those of preexisting stable spines to determine the molecular signature of new spines formed during learning. Aim 2 identifies the presynaptic partners for learning-associated new spines, and dissects how local circuits reweigh or rewire during learning. Aim 3 investigates how spine dynamics of pyramidal neurons from different cortical layers respond to motor learning, and determines if new spines formed during learning receive unique presynaptic inputs. Successful completion of the research will not only provide critical insights into the biology of synapse formation and diversity, but also offer neuroscientists a novel tool box to highlight new connections formed in a brain's recent past. Discovering how synapses remodel during learning will build a foundation for future investigation of how synaptic structure/function is altered by pathologies associated with learning defects.

An award is made to the University of California Santa Cruz to add long-wavelength excitation light (1,550 nm) and adaptive optics (AO) into a commercial multiphoton microscope (Olympus) for live deeptissue biological imaging. Adaptive optics has provided diffraction-limited images for large ground-based telescopes by correcting for the blurring caused by the atmosphere. They propose to re-apply similar adaptive optics techniques in multiphoton microscopy to obtain diffraction-limited images from deep within living biological tissues. This development will provide biologists with new imaging capabilities, similar to advantages adaptive optics provided to astronomers, enabling them to obtain the highestresolution deep-tissue images in neurobiology to study brain development and synapse plasticity in the nervous system, in cell biology to study cell cycle events, and in developmental biology to study stem cells, chromatin remodeling and the cytoskeleton. The research activities in this project include opportunities for undergraduate and graduate students to participate in a multidisciplinary research team consisting of optical physicists, electrical engineers, and biologists, contributing to their training as the next generation of instrumentalists and advanced users. The research activities and instrumentation will be integrated into teaching at the undergraduate and graduate levels through hands-on projects in engineering and science courses at UCSC, a Hispanic Serving Institution (HSI), and through an NSF sponsored outreach program, the California State Summer School for Mathematics and Science(COSMOS), a summer residential program for high school scholars with demonstrated interest and achievement in math and science. They will also work in a partnership with all ten UC campuses and three affiliated national labs (LANL, LBNL, and LLNL) and industry to broadly disseminate the technology to the biological research community. Such improvements will benefit society by greatly advancing our fundamental understanding of life processes at the cellular and sub-cellular levels.

The proposed activity more than doubles the depth (>1,500nm) of diffraction limited imaging (738 nm) into dynamic live tissue (AO frame rate >1 Hz) where many fundamental cellular processes occur, such as neuron growth, organization and synapse formation. For example, by increasing the imaging depth from 500 um to 1,000 um, they can reach the deeper cortical layers to see if synaptic reorganization during development and under pathological conditions follows similar rules as in the superficial cortical layers, were synapses are constantly remodeling in living animals. By increasing the imaging depth beyond 1,000 um they can reach the Hippocampus, the site for learning and memory. This will allow studies of how synapses reorganize during learning and how they encode for long-lasting memory.

Proposal: 1607245
PI: Zuo, Yi


Funding is requested to support two symposia of the 2015 International Chemical Congress of Pacific Basin Societies (Pacifichem), to be held in Honolulu, Hawaii, Dec. 15-20, 2015. These two symposia are Safety and Sustainability of Nanotechnology (#404) and Interfacial Phenomena For Bubbles, Droplets, Films and Soft Matter (#403). The requested funding will be used to provide travel awards to outstanding graduate students and non-tenured junior faculty members. At the conclusion of this conference, the PI will work closely with co-organizers and speakers to publish a symposium proceeding and one review or commentary to highlight the state-of-the-art of surface sciences, nanosafety and major issues discussed in these symposia.

The symposium of Safety and Sustainability of Nanotechnology aims to bring together chemists, biologists, engineers, and legislators to discuss necessary precautionary approaches of nanotechnology and to stimulate cost-effective measures to prevent environmental and health degradation. The particular focus will be on safety and sustainability of nanotechnology. The symposium of Interfacial Phenomena for Bubbles, Droplets, Films and Soft Matter aims to explore fundamental colloidal and interfacial phenomena and their role in a variety of physical chemistry and biophysical areas, such as smart surface, self-assembly and bionanotechnology. Both symposia are multidisciplinary and have far-reaching impacts on multiple scientific disciplines. The symposium of Safety and Sustainability of Nanotechnology will outreach four interdisciplinary research themes, i.e., nanotoxicology, nanomedicine and bionanotechnology, sustainable nanotechnology, and policy/regulation of nanotechnology. The symposium of Interfacial Phenomena for Bubbles, Droplets, Films and Soft Matter will cover three research areas, including colloid and surface science, bio-related soft matter, and molecular assembly of biomimetic systems.

Project Summary Fragile X Syndrome (FXS) is the most common type of mental retardation that can be linked to a single gene mutation. FXS patients exhibit many behavioral alterations, as well as abnormal development of synapses in the brain. Astrocytes, the major type of glia in the mammalian brain, regulate synaptic and neuronal functions and are implicated in many developmental and degenerative neurological diseases. The goal of this proposal is to determine the roles of astrocytes in FXS. Combining mouse genetics, live imaging, synaptic molecular profiling, behavioral analyses and pharmacological intervention, we propose 3 aims. In Aim 1, we study how astrocytic deletion of Fragile X Mental Retardation Protein (FMRP) contributes to the synaptic and behavioral defects observed in mice. We will generate transgenic mice in which FMRP is selectively deleted or exclusively expressed in astrocytes. We will then compare the synaptic and behavioral phenotypes of these mice with those of wild-type controls and FMRP full knockout mice. Aim 2 builds upon our earlier observation that astrocyte-specific FMRP knockout mice have increased production of immature dendritic spines of cortical neurons. We will combine in vivo imaging with mathematical modeling and synaptic proteomic imaging to address how astrocytic deletion of FMRP affects the spatial distribution of spinogenesis on excitatory cortical neurons, as well as synaptic/peri-synaptic neuronal and astrocytic protein expression of newly formed spines. In Aim 3, we examine the functional changes of synapses in mice in which FMRP is selectively deleted in astrocytes. In particular, we will examine how glial glutamate uptake and synaptic glutamate concentration are affected in astrocyte-specific FMRP knockout mice, and determine if correcting abnormal glutamate uptake alleviates the dendritic spine defects in these mice. The proposed work will be the first systematic in vivo study investigating astrocytic contribution to FXS. By examining the role of astrocytes in the neuropathology of FXS, these studies will advance our understanding of the disease and potentially point out new therapeutic targets.

Scientists first proposed in 1895 that water transport in plants often occurs under negative pressure, which is generated though surface tension in the cell walls of leaves and which causes water to flow from the soil into the roots and as sap up towards the leaves. Much evidence has accumulated since then to support this hypothesis, known as the cohesion-tension theory, but it is still unknown how plants can move water under negative pressure without constantly creating bubbles in their hydraulic system, the xylem. The question how negative pressure transport works in plants has achieved new urgency with the recent discovery of surfactants in the sap. This finding contradicted the assumption that sap is essentially pure water, and that the high surface tension of water prevents bubbles from forming or from entering the hydraulic system through small pores in xylem walls. This research will determine the chemical composition of xylem surfactants, characterize their physical properties, including surface tension, locate surfactant micelles and their cellular origin in the xylem, and survey a number of plant species from different evolutionary backgrounds to determine if xylem surfactants are ubiquitous in vascular plants. Broader impacts of the project include involvement of several undergraduate and graduate students in the research, including many from groups underrepresented in science. The research has the potential to result in biomimetic applications, such as solar-powered microfluidic devices that transport liquids under negative pressure.

Previous findings have shown that xylem sap of woody angiosperms contains insoluble surfactants, including numerous proteins, glycoproteins, and phospholipids. The proposed research is motivated by a new hypothesis that insoluble surfactants enable water transport under negative pressure by controlling bubble sizes to remain smaller than a critical threshold size, below which bubbles do not expand to form embolisms. Such a mechanism could explain how it is possible to transport large amounts of gas-saturated or super-saturated water under normal, non-stressed conditions, down to several MPa of negative pressure, a feat that human engineers have been unable to replicate. The aim of the research is to characterize xylem surfactants and determine how common they are in vascular plants, including angiosperms and gymnosperms, because this information is needed before any hypotheses about their functions in plants can be tested. Methods will include lipidomic and proteomic studies of xylem sap, constrained drop surfactometry of xylem surfactants, and electron microscopy of xylem sap and xylem to locate surfactant micelles and their origin in the xylem.

PI: Zuo, Yi
#1604119
The rapid development of nanotechnology and a widespread proliferation of nano-enabled consumer products post an increasing concern of the potential adverse environment, health, and safety (EHS) impacts of nanoparticles (NPs), which feature a characteristic size less than 100 nm. Most NPs are lightweight and respirable. Once inhaled, NPs can penetrate into the lungs and interfere with the respiratory function. The entire surface of the lungs is lined with a lipid-protein pulmonary surfactant (PS) film which serves an important physiological function of host defense and surface tension reduction. Interactions between inhaled NPs and the PS film hence represent the initial nano-bio phenomena in the lungs. Such interactions determine the fate of the inhaled NPs and their potential therapeutic or toxicological effects. This proposal will investigate the detailed mechanism of NP-PS interactions using novel experimental and computational techniques developed in the PI's laboratory. These techniques allow high-fidelity simulations of air pollution scenarios in which NPs are inhaled and deposited at the surface of the PS film. Using these model systems, potential environmental hazards of NPs and nano-enabled products, such as NP-containing sprays and paints, will be thoroughly evaluated. The PI will specifically focus on studying the potential risk of respirable NPs for infants and children whose fragile respiratory system makes them more vulnerable to NP exposure than adults. The proposed study will help provide a useful metric for regulating and overseeing commercial applications of nanotechnology towards a safer and sustainable development.

The research goal of this proposal is to study the detailed biophysicochemical mechanisms by which airborne engineered nanoparticles (NPs) interact with natural pulmonary surfactant (PS). This research is highly novel due to the following two main perspectives. First, NP-PS interactions will be studied using a combined approach of multiscale in vitro and in silico simulations. The in vitro study relies on biophysical simulations using a novel experimental methodology recently developed in the PI's laboratory. With this in vitro model, nano-bio interactions at the PS film will be mimicked with fully controlled NP aerosol dosimetry and under physiologically relevant respiratory conditions. The in silico study relies on high-fidelity molecular dynamics simulations which allow probing the detailed molecular mechanism of NP translocation across the PS film. Second, the PI will carry out the first comprehensive study of the biomolecular corona bound to NPs in contact with lung fluids, i.e., the so-called PS biomolecular corona. With correlated high-precision mass spectrometry and molecular dynamics simulations, the proposed project will reveal the biochemical composition and biophysical conformation of the PS biomolecular corona with unprecedented details. This research is expected to significantly advance current understanding of nano-bio interactions in the respiratory system and to provide novel insight into the EHS impacts of nanotechnology.

The broader impacts of this proposal are rich and multifarious. In vitro and in silico simulations developed in this proposal are cost-effective means of exploring the EHS impacts of nanotechnology. The proposed study will complement the current nanotoxicological knowledge obtained from cell culture and animal-models. The biophysicochemical mechanism revealed by this study has clear transformative values for designing NP-based pulmonary drug delivery and for better understanding the pathophysiology of respiratory diseases related to air pollution and particle insult. In collaboration with local healthcare providers, the PI is engaged in activities of increasing the public awareness of the potential risk of respirable NPs for infants and children. Given the unique location of the University of Hawaii, the PI is dedicated to promoting participation of Native Hawaiians, Pacific Islanders, and students from other underrepresented groups and low-income families. The PI will also develop undergraduate and graduate engineering curricula with interdisciplinary components, and help enhance the infrastructure for research and education.

Project Summary The gut microbiota, a community of symbiotic bacteria, fungi, and archaea residing in the mammalian gastrointestinal tract, plays an integral role in the neurodevelopment and neurophysiology of the host. Its disruption has been associated with neurodevelopmental and neurodegenerative diseases. Microglia are the resident immune cells in the central nervous system; they are continually influenced by gut microbiota, raising the possibility that microglia dysfunction may be the link between dysbiosis and altered brain functions. This proposal investigates how early-life exposure to penicillin, the most-used antibiotics in perinatal medicine, affects the interplay between gut microbiota, the immune system, cortical development, and sensory processing in mice, and explores the potential of probiotics as a preventative measure. Aim 1 studies how perinatal penicillin exposure (PPE)-induced gut dysbiosis affects cortical microglia and sensory processing in adolescent and adult mice. It also explores whether early postnatal normalization of gut microbiota prevents microglia activation and behavioral defects later in life. Aim 2 studies how PPE alters microglia motility, their synaptic contact, synapse pruning, and cortical neuronal activities associated with the defective sensory processing. This study will advance our understanding of the gut-immune-brain axis in neural development, circuit function, and behavior, with significant relevance to clinical medicine and public health.

A large body of literature has resulted from research on interactions between nanomaterials and biological and ecological systems. As a consequence of these research activities, current regulations are being examined for adequacy. The overall goal of these symposia is to promote collaboration and discussion across multiple disciplines related to nanotechnology. These symposia will help bring together chemists, biologists, engineers, and legislators to discuss the necessary approaches and to discuss cost-effective measures to prevent unintentional environmental and health degradation as a result of the widespread use of nanomaterials. Support for these symposia will provide outstanding graduate students and participants with travel funds to attend the 2020 International Chemical Congress of Pacific Basin Societies, to be held in Honolulu, Hawaii, December 15-20, 2020. The awarded graduate students and participants will be selected by a scientific committee based on the intellectual merit and the broader impacts of their research. To promote diversity, equity and inclusion, students and participants from traditionally underrepresented groups will be given high priority. The awarded students and participants will have the opportunity to expose to be a variety of scientific topics, including but not limited to nano-bio interactions, nanotoxicology, nanomedicine, colloid and surface science, particulate matter, smart surfaces, self-assembly, 3D printed organs, and bionanotechnology. Particular focus will be on understanding and designing safe nano-bio interfaces for materials, medicine, and the environment. These symposia will provide students and participants with an excellent opportunity to communicate research and education activities in the area of nanotechnology.

The PI will seek participation from distinguished researchers and students in four symposia within the 2020 International Chemical Congress of Pacific Basin Societies (Pacifichem), which will be held in Honolulu, Hawaii, December 15-20, 2020. These four symposia are (1) Understanding and Designing Safe Nano?Bio Interfaces for Materials, Medicine, and the Environment, (2) Interfacial Phenomena for Bubbles, Droplets, Films and Soft Matter, (3) Peptide Self?Assembly: Chemistry and Nanotechnology, and (4) 3D Printing in Chemistry, Biology and Materials. All four symposia are highly interdisciplinary and have far-reaching impacts on multiple scientific disciplines. This support will provide students and participants with a unique opportunity to attend the Pacifichem 2020, and to learn the state-of-the-art knowledge of nanotechnology and nanosafety. The PI will disseminate knowledge to the academic community and the industry through the publication of review and commentary articles that will highlight the state-of-the-art of nano-bio interactions, colloid and surface sciences, self-assembled peptides and nanomedicine, additive manufacturing, and other major topics discussed in these symposia.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Understanding the complex behavior and interaction between extremely tiny particles (nanoparticles) and living organisms is of crucial importance in advancing the science of drug delivery, as well as proactively preventing the environmental, health and safety ramifications after inhalation of noxious gases and/or infectious airborne particles. Once inhaled, nanoparticles immediately adsorb biological molecules normally found in the surface lining of the lung, enveloping the nanoparticle with a unique biomolecular corona that defines its subsequent cellular interactions. To date, little is known about the biological and physicochemical driving forces regulating the formation of the biomolecular corona. It is also unknown what potential deleterious effects may result from the interactions of these corona-covered particles on the human lung. Thus, the goal of this research project is to develop novel experimental methods for understanding the thermodynamic driving forces responsible for the formation of the biomolecular corona of inhaled nanoparticles. Understanding the dynamics of these pulmonary/nanoparticle interactions will provide novel insights into the mechanism of pulmonary toxicity of inhaled nanoparticles. By collaborating with local healthcare providers, the overarching goal is to apply the knowledge gained from this research to elucidate the environmental risks of a library of nanoparticles, particularly those that are likely to adversely affect the lungs of infants and children. Through the unique location of the University of Hawaii, the investigator is dedicated to promoting participation in this research with Native Hawaiians, Pacific Islanders, and students from underrepresented minority groups.

The objective of this research project is to test a novel hypothesis that the surface free energy of nanoparticles regulates the structure and chemical composition of the pulmonary surfactant biomolecular corona, using a combined experimental and computational approach. Although it is well known that the hydrophobicity of nanoparticles plays a critical role in defining the structure and chemical configuration of the biomolecular corona, the biomolecular events have never been elucidated or systematically studied. This is largely due to the lack of quantitative methods for characterizing the hydrophobicity of nanoparticles. The PI will fill this gap by developing a novel optical method for determining the surface free energy of nanoparticles as a quantitative measure of its hydrophobicity. This method relies on an innovative measuring principle of manipulating the intermolecular forces between nanoparticles across liquid media. The methodology is both unique and innovative, and distinctly different from existing methods. Once developed and validated, it has the potential to offer a standard, low-cost, and easy-to-use method for quantitatively characterizing the surface free energy and hydrophobicity of particulate matter. The PI will experimentally study particle-size dependent surface free energy, and the energetic effect of the biomolecular corona utilizing a library of pristine nanoparticles. Knowledge from this study will provide insight into the thermodynamic driving forces at play in the formation of the biomolecular corona. This research will also advance the current understanding of the nano-bio interaction in the lungs and bridge the gap between the available biophysicochemical data and nanotoxicological data. Broader implications include a translational research methodology and approach in designing nanoparticle-based pulmonary drug delivery systems and in furthering an understanding of the pathophysiology of respiratory injury caused by noxious air pollutants and other environmental respiratory hazards. Ultimately, the developed technology offers the potential for widespread usage in many platforms, both in the laboratory and in studies performed on humans to improve respiratory health. The PI is actively engaged in the Native Hawaiian Science & Engineering Mentorship Program (NHSEMP) and the Society of Women Engineers (SWE) at the University of Hawaii. The PI will support one graduate student and several undergraduate students from traditionally underrepresented groups.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

Project Summary The improvement in living standards and the advancement in modern medicine have greatly extended human life expectancy. However, aging-related functional decline and diseases, in particular cognitive impairment and neurodegeneration, also become more prevalent. Studies of heterochronic blood exchange reveal that the aged systemic milieu inhibits neurogenesis and impairs cognitive functions in young animals, suggesting the existence of age-elevated systemic factors detrimental to brain health. In particular, inflammation may become excessive and chronic with aging (?inflammaging?) and impair normal brain functions. Thus proteins involved in inflammatory responses, such as cytokines, are candidates of such systemic factors implicated in brain aging. Building upon published literature and our recent finding, we hypothesize that aging-associated alterations in systemic inflammatory factors activate microglia (resident immune cells in the central nervous system) and lead to microglia-mediated synapse loss; restoring the expression pattern of such factors to the healthy young state rescues synaptic defects and improves cognitive functions. In Aim 1, we will use bio-orthogonal non- canonical amino acid tagging (BONCAT) to determine how treatment with a cocktail of Alk5 inhibitor (Alk5i) and oxytocin (OT, a neurotrophic, anti-inflammatory peptide) or heterochronic blood exchange affects the expression profile and distribution of inflammaging-related systemic factors in the brain and peripheral tissues. Aim 2 examines how Alk5i+OT treatment and heterochronic blood exchange affect neuro-immune interaction in the brain, taking advantage of in vivo two-photon imaging to study microglia-synaptic interactions and their effects on synaptic integrity and dynamics in the cortex. Using Array Tomography, a high-throughput, super- resolution proteomic imaging technique, Aim 3 conducts molecular dissection and reconstruction of large populations of individual synapses and determines the effect of Alk5i+OT treatment and heterochronic blood exchange on synaptic molecular signatures and inflammatory cytokine distribution in the brain. Together, these studies will provide a comprehensive characterization of age-specific effects of blood on the brain proteome and synaptic circuits, and outline candidate mechanism(s) responsible for brain aging.