Daniel Goldman, Ph.D. - US grants

DESCRIPTION (provided by applicant): The molecular mechanisms by which synapses form during development and are modified in the adult are largely unknown. Understanding the mechanisms by which cell-cell interactions at the synapse influence synaptic protein expression will provide insight into synaptogenesis and synapse modulation. The long term goal of this research application is to characterize these mechanisms. The neuromuscular junction provides an ideal system for studying these processes since it is homogenous, accessible to experimental manipulation and is the best studied synapse in the nervous system. The nicotinic acetylcholine receptor (nAChR) mediates communication across this synapse and serves as an excellent marker for studying pre- and post-synaptic cell interactions regulating synaptic protein expression. During development, nerve-induced muscle electrical activity suppresses nAChR gene expression in extrajunctional regions of the muscle fiber, while nerve-derived factors induce nAChR gene expression at the endplate. In this application we propose to focus on activity-dependent control of nAChR gene expression. Protein kinase C (PKC) is proposed to mediate activity-dependent suppression of nAChR gene expression in birds, however no such evidence exists for mammalian muscle. We will characterize PKC activity in active and inactive muscle and determine if inhibition or activation of specific PKC isoforms can influence nAChR gene expression in mammalian muscle. Calcium suppresses nAChR gene expression via DNA sequences mediating activity-dependent regulation. Calcium's effect appears to be independent of PKC and may be mediated, in part, by calcium/calmodulin-dependent protein kinase. Therefore we will characterize the mechanism by which calcium regulates nAChR gene expression and determine if this regulation also participates in activity-dependent control of these genes. In addition to myogenin, SP1 also activates nAChR gene expression and may interact with myogenin. We propose to characterize the mechanism by which SP1 mediates increased nAChR gene expression and if this SP1-dependent regulation is controlled by muscle activity. Finally, we will determine if myogenin and SP1 phosphorylation is regulated by increased intracellular calcium and muscle depolarization and we will map these putative phosphorylation sites.

This project aims to test our hypothesis that S1, a sister gene of EF- 1alpha, functions as a candidate "maintenance gene" to maintain the long-lived and terminally differentiated state for myotubes in mature muscle. During development in muscle, S1 expression is activated with a concomitant decline in EF-1alpha protein, but not message, level, suggesting a posttranscriptional suppression of the regulation of EF- 1alpha abundance, and resulting a shift in EF-1alpha ratio from high to low. The low EF-1alpha/S1 ratio persists in adult muscle except in the cases of marcaine-induced injury, long-term denervation, or extreme old age. We also found that stable transfection of S1 into S1- negative mouse fibroblasts induces suppression of endogenous EF- 1alpha. Experiments planned are to test our working hypothesis that in myotubes, S1 may function as a "dimmer switch", dampening EF- 1alpha activity by reducing its protein abundance via translational suppression and/or rapid protein turnover. This dampening action may leave EF-1alpha restrained in not only its traditional function in protein translation, but also other known functions such as involvement in signal transduction, severing microtubles, or bundling actin filaments, all of which may result in establishing an even gear range favorable to the long-term nonapoptotic state in mature muscle. The specific aims formulated are: 1. To test whether posttranscriptional suppression of EF-1alpha protein level in adult muscle is developmentally-and S1 gene expression-dependent; 2. To determine the regulatory mode for the posttranscriptional suppression of EF- 1alpha protein level; 3. To investigate how S1 gene expression is related to this suppression of EF-1alpha protein abundance, and to identify responsible putative cis-element(s) and trans-factor(s); 4. Testing, in cultures, the hypothesis that muscle fibers' atrophy is due to myotube apoptosis and replicative senescence of the satellite cell population; 5. to test the hypothesis that a change from low to high EF-1alpha/S1 ratio is involved in the activation of death in cultured myotubes; and 6. To investigate the regulatory mechanism(s) governing the shift of EF-1alpha/S1 ratio from low to high during injury, long-term denervation, and aging. Studying the mechanism(s) regulating the EF-1alpha/S1 ratio will ultimately allow the design of molecular manipulation to control or slow down muscle degeneration, a condition plaguing most of the elderly.

"Collaborative Research. Graptolite Macroevolution: Phylogenetic Analysis
and Testing Hypotheses of Directional Change".
Charles E. Mitchell and Daniel Goldman.

One of the most contentious issues in evolutionary theory is the notion of progress. Some scientists have argued for a qualified expectation of progress in the evolution of major groups while others have argued that we should expect evolutionary histories that are dominantly non-progressive. Efforts to quantify evolutionary patterns have produced conflicting results. Thus, the question of whether natural selection leads to long-term progressive trends remains controversial and frustrating.
The central goal of the proposed research is to determine if there were significant progressive evolutionary trends within a group of fossils called graptolites. Graptolites are a group of extinct marine organisms that flourished from approximately 505 to 310 million years ago. The graptolite fossil record offers an outstanding opportunity to make a rigorous test of directional evolution for two reasons. First, graptolite evolutionary patterns have long been used as textbook examples of progressive evolution. Secondly, the fossil record of graptolites is exceptionally good, and their temporal and biogeographic distributions have been intensively studied.
The work proposed here is expected to contribute substantially to an increased understanding of the mechanisms of graptolite evolution and their pathways of descent. It is also expected that it will lead to improvements in the methods paleobiologists employ to study evolutionary pattern and process. Both of these outcomes are likely, it is thought, to positively effect the broader issue of testing the fossil record for evidence of progress in evolution and the means by which it might occur.

DESCRIPTION (provided by applicant): Despite structural and functional similarities between the teleost and mammalian retina, disease or injury of the mammalian retina leads to irreparable vision loss, while the injured teleost retina mounts a regenerative response that restores lost sight. Key to successful regeneration is Muller glia (MG), which dedifferentiate and generate retinal progenitors that can regenerate all major retinal cell types. In contrast, mammalian MG responds to retinal injury by reactive gliosis that is accompanied by hypertrophy; rarely do these cells re-enter the cell cycle and regenerate new neurons. These data suggest that a key difference between the regenerative responses of fish and mammals is the ability of MG to dedifferentiate following retinal injury. We propose that an understanding of the mechanisms by which MG dedifferentiate and generate a proliferating population of retinal progenitors will suggest novel strategies for stimulating this process in mammalian MG. Because zebra fish mount a robust regenerative response following retinal injury, they provide a useful model system for uncovering these mechanisms. This proposal focuses on uncovering secreted signals and receptors that stimulate MG dedifferentiation, mechanisms by which these signals are transmitted to the genome and mechanisms underlying proliferation of MG-derived progenitors. In addition, new zebra fish models have been created to test whether ablation of any retinal cell type is sufficient to induce MG dedifferentiation and retina regeneration and if any cells can compensate for loss of MG during retina regeneration. These studies should lead to novel strategies for inducing MG dedifferentiation and retina regeneration in mammals which can be applied to repairing a damaged or diseased human retina.

The ability to develop legged robots that can effectively run over flat, inclined, uneven and deformable surfaces is critical to a wide range of civilian (e.g., search and rescue) and military (e.g., reconnaissance, mine detection) applications. This task has proven particularly problematic to traditional control strategies, yet many animals, unlike their synthetic counterparts, are able to transcend complex environments such as jungles, caves, deserts, buildings, and piles of rubble with remarkable ease. Despite their miniscule size, insects can function in almost any environment by means of their ability to climb, crawl, or run as the situation demands. Although recent progress has been made in the development of bio-inspired robots capable of locomotion over uneven ground, and others that can (slowly) climb sheer surfaces, no legged machines currently exist that can dynamically operate in a combination of vertical and horizontal regimes. The recent discovery that rapidly climbing cockroaches and geckos utilize their legs to actively pull the body toward the feet, rather than pushing the body away as in running, has inspired a new dynamic model for vertical running and the construction of the first dynamic climbing robot. The salient feature of this climbing model and robot is the intentional utilization of large lateral pulling forces when rapidly climbing. Since these pulling motions observed experimentally do not appear to provide an obvious energetic advantage, we hypothesize that this type of side to side climbing is driven primarily by stability considerations. This project pursues an integrated study of insect biomechanics, dynamic modeling, and robotic synthesis to determine the importance and proper utilization of lateral oscillations in running and climbing over various degrees of incline.

The study seeks to answer these questions not only to provide insight into animal biomechanics, but also to produce guiding principles that can be utilized to develop the next generation of dynamic legged robots. In particular we aim to understand the connection between neuromuscular control strategies in insects and functional performance in changing environments (i.e. slope and substrate), develop reduced order models to determine how lateral motion pattern contribute to improved stability and locomotion performance, and develop a novel robotic test platform to empirically test the predictions of the bio-inspired locomotion models and provide insight into how lateral dynamics can be explicitly utilized to improve the mobility of legged robots over varying terrain and substrates.

In this proposal the PI will study how a desert dwelling lizard, the Sandfish, swims beneath the surface of a granular material. Imaging methods will be developed to surmount the difficulties of visualizing biological systems in opaque terrestrial media and computational modeling tools will be created to study the interaction of the organism with materials whose equations of motion are unknown. These efforts will occur in three interacting thrust areas: (1) Measurements of organism motion and dynamics: A multiplane, high speed and resolution x-ray imaging system will be built to obtain the first three dimensional kinematics of an organism moving within a complex medium. Both the kinematics and forces will be characterized as the substrate properties are systematically varied by use of an air fluidized bed. (2) Physics experiment to characterize response of granular media to swimming motions: Developing models of the locomotion will require understanding the physics of the material response in this regime in which the bulk of the material behaves like a solid except for a small region surrounding the organism which behaves like a fluid. The forces associated with maneuvering objects through the granular medium will be measured and the results use to produce an empirical model of force production. (3) Computer models of organism and granular media: As granular media are amenable to direct numerical simulation, development of a 3D Molecular Dynamics simulation interacting with the actuated objects (lizard models) used in experiment will result in numerical environment interaction models that can be used to interrogate the motion at the grain level as well as to create the first models of biological organisms moving within this material. The experimental data obtained from studying the organism will suggest actuation strategies that will be played through the physics experiments and validated models. This study will initiate the beginnings of a deeper understanding of movement within non-Newtonian media and thus will result in a new model system for locomotion biology, as well as models for locomotion. This work will create rapid modeling tools to aid design of robotic exploration and search & rescue devices that must burrow through challenging terrain. It will also gather students from a diverse range of backgrounds: physics students will interact with biology students to make progress on experiments and models. This program will serve as a springboard to develop a course examining control of locomotion, mechanical properties of biological actuators (muscle), skin friction, rheology of complex matter, etc. Outside the university, the program will provide outreach by engaging the public in visible and graspable science.

DESCRIPTION (provided by applicant): Synaptogenesis is regulated by both activity-dependent and independent mechanisms. Activity-dependent regulation of synaptogenesis is mediated, in part, by changes in gene expression. Therefore an important goal of neuroscientists is to understand the mechanisms by which synaptic activity is transduced to the genome to influence synapse formation. The neuromuscular junction (NMJ) is a well studied model for identifying and characterizing the mechanisms by which synaptic activity influences synapse formation and regulates gene expression. Although activity-dependent control of NMJ formation has been studied for decades, the underlying molecular mechanisms are poorly understood. We recently identified a Dach2-dependent signal transduction cascade that contributes to activity-dependent expression of nAChR and MuSK genes. Therefore, this signaling cascade along with the previously reported HDAC9 (MITR) signaling cascade, that also participates in activity-dependent nAChR gene expression, represent good candidates for mediating the effects of synaptic transmission on NMJ formation. In this grant application we propose to use a combination of genetic approaches and cell and molecular biological approaches to investigate the role Dach and MITR signaling play in regulating NMJ formation and controlling gene expression by nerve-induced muscle depolarization. Knockout animals will be used to study NMJ development, while innervated and denervated skeletal muscle will be used to study nerve-induced, activity-dependent gene regulation. Specifically, we propose to: 1) Evaluate the role Dach2 and MITR play during development of the NMJ; 2) Examine if HDAC4 coordinates Dach2 and MITR gene repression in response to muscle innervation; and 3) Determine if the Dach interacting proteins Six and Eya participate in activity-dependent regulation of gene expression. This research will identify mechanisms by which muscle activity regulates synapse formation during development and modifies synapse and muscle function in the adult. Although this research is of a basic nature, it may suggest ways of enhancing synapse formation, synaptic plasticity and muscle function in the injured, diseased or aged individual. PUBLIC HEALTH RELEVANCE: The studies in this grant application aim to understand how muscle activity signals to the genome to regulate neuromuscular development, muscle atrophy and muscle gene expression. These studies will not only further our understanding of the mechanisms underlying these events, but may also suggest novel strategies for restoring neuromuscular communication and improving muscle function following injury or disease.

In this project the PIs will use laboratory experiments and simulations to systematically study how the behavioral and physical interactions of fire ants (Solenopsis invicta) with cohesive granular media influence the formation of underground nests. The specific objectives are: (1) To study how ant colonies build and respond to perturbations in different media. (2) To understand how ground properties affect nest structure and stability. (3) To study multi-agent simulation models of nest formation. A major problem in modeling nest construction is that the physics of cohesive soils is not sufficiently developed to predict stability of structures. To address this question the PIs will combine information from the first two aims into a multi-agent simulation to model nest formation; individual behavioral rules will be derived from observations and cohesive soil rule will be derived from physics studies. These will be integrated to form a minimal physical model using granular physics simulation and ant grain interaction that captures the observed nest formation and allows the testing of different hypotheses of colony function. The PIs will coordinate with high schools serving populations underrepresented in the sciences to recruit teachers into the research labs and place graduate students into local high schools as teaching assistants. In addition they will also institute engineering-science team projects for undergraduates so that students gain a better understanding of interdisciplinary research at the intersection of biology and physics. The proposed experiments and models can aid in controlling invasive species such as S. invicta by learning how soil modification affects nest building. The multi-agent simulations will be of use to many outside this field for solving scientific or engineering problems. In addition this research program will provide a platform for modeling bioturbation, a major factoring affecting planetary ecology.

Collaborative Research: Graptolite Biogeography, Paleo-GIS, and Evolutionary Dynamics of Early Paleozoic Zooplankton

Daniel Goldman, Dayton University, EAR-0958372
Charles Mitchell, SUNY, Buffalo, EAR-0958308
H. David Sheets, Canisius College, EAR-0957672

ABSTRACT
Deep-time perspectives on climatic and oceanographic change are critical for understanding the long-term controls on environmental processes. This is particularly the case for the 'tipping points' that lead to episodes of climatic extremes, events that are often associated with episodes of profound biodiversity change. The spatial and temporal distribution of planktic organisms has proven to be critical to the reconstruction of climatic and oceanographic conditions during the Mesozoic and Cenozoic. The oldest geological period for which there is a diverse and abundant record of zooplankton is the Ordovician, and that record is provided by graptolites. PIs objectives are to analyze the changing biogeographic distribution patterns in graptolites from the mid-Ordovician into the lower Silurian using newly developing global databases, ecological modeling, and paleo-GIS techniques. Graptolite spatial distribution patterns should help understand the relationship between ancient ocean structure, climate, and zooplankton biogeography. Strong parallels have recently been drawn between the glacial-interglacial cycles of the Late Ordovician-Early Silurian and those of the late Cenozoic. Therefore, understanding the biogeographic and biodiversity changes associated with these climatic cycles will provide insights relevant to our understanding of biotic response to recent and modern climate change. Although this study will focus on the Ordovician and Early Silurian biosphere and its interconnections, the questions PIs propose to pursue - how range area and spatial patterning of faunas affect or respond to changing environmental history and species evolutionary dynamics - are fundamental questions that biologists and paleobiologists are pursuing across our traditional disciplinary boundaries of taxon, age, and conceptual approach.

In this project the PI will develop a neuromechanics of locomotion on dry and wet granular substrates. This will be used to address how effective movement results from the interaction of body morphology and posture, muscles, Central Pattern Generators (CPG), and sensory systems with the physical features of complex environments like solidification and fluidization. The PI will study three organisms -- sandfish lizards, zebratailed lizards, and salamanders -- that respectively swim, walk and run effectively within and on granular substrates. These organisms will be chosen as representatives of effective locomotion in a given substrate: the sandfish swimming in sand, the zebra-tailed lizard sprinting over a diversity of granular terrain, the salamander walking in mud. The salamander also embodies features thought to be representative of early tetrapods. The project will use high speed imaging (both visible light and x-ray), granular force platforms, and electromyography (EMG) to record kinematics, dynamics, and muscle activity. The PI will develop controlled granular substrates using fluidized beds which will allow both creation of repeatable initial conditions and rapid perturbations to generate neuromechanical control hypotheses. Robotic models of organisms to test hypotheses will be built as well. The models will have relevance to organisms in the present and will be a step toward development of quantitative hypotheses of the evolution of movement on land. Understanding of the physics of soft materials like mud and wet sand will be enhanced. The work also has clear implications for robotics; in the modern world, in which disasters are common and affect many lives, there is a pressing need for devices that can explore complex shifting terrain. The PI will use the robots from the locomotion research to create hands-on robot modules to teach science by: 1) Developing and teaching a course in hands-on experimental science for undergraduates emphasizing principles of mechanics, electronics and biology. 2) Bringing K-12 teachers to Georgia Tech in the summer to learn to use hands-on locomoting robot kits. 3) Developing "Robotics Inspired Science Education" (RISE) nights to utilize robots to generate interest and teach principles of science to the public.

DESCRIPTION (provided by applicant): Unlike mammals, zebrafish are able to regenerate a damaged retina and restore lost sight. This regenerative ability depends on Muller glia (MG) that respond to retinal injury by undergoing multiple shifts in identity as they dedifferentiate, proliferate, and finally differentiate to regenerate new neurons and glia. Although MG can be coaxed to proliferate in the injured mammalian retina, they do not exhibit multipotency and only rarely regenerate damaged neurons. Therefore understanding the mechanisms driving zebrafish MG reprogramming to mutlipotency may suggest novel strategies for generating multipotent progenitors from mammalian MG. Recent studies suggest that MG reprogramming is accompanied by activation of gene expression programs that are similar to those acting in embryonic stem cells and retinal progenitors. We hypothesize that genetic programs driving MG dedifferentiation and multipotency are controlled by DNA methylation. In animals, DNA methylation predominantly occurs at CpG dinucleotides and controls transcriptional regulatory processes like imprinting, X-chromosome inactivation, transposon silencing, and stable silencing of gene activity. Methylation of DNA proximal to gene-coding regions is correlated with gene silencing. Importantly, changes in DNA methylation have been correlated with the activation and suppression of gene expression programs that take place during early development and accompany the reprogramming of somatic cells to yield induced pluripotent stem cells. It is likely that erasure and reestablishment of genomic methylation, at key locations, accompanies the gene expression changes that drive MG dedifferentiation and multipotency and subsequently the regeneration of new retinal cell types. Here we propose to identify regions of the MG genome that are undergoing methylation changes during retina regeneration and determine if these changes correlate with gene expression changes that have previously been characterized using microarray technology. In addition, we propose to test the hypothesis that DNA demethylation in dedifferentiating MG is an active process driven by Apobec2a and 2b proteins.

PI: Philip Benfey (Duke University)

CoPI: Daniel Goldman (Georgia Institute of Technology)

The goal of this EAGER project is to begin to address the question "How do plant roots behave in soil?" Due to the opaque nature of soil, most previous studies have involved digging up roots, observing them in transparent materials, or observing them as they grow against a transparent interface. This project is an early stage effort that has the potential to transform the way root/soil interaction studies are performed. Expertise in the physics of granular matter will be combined with expertise in root biology to explore this area. The experimental plan involves growing rice in cylindrical containers and systematically varying soil parameters. Root response will be imaged with X-ray computed tomography with 3-D root structure reconstructed and analyzed using software previously developed by the PIs.

The project is interdisciplinary (physics and biology) and applies new expertise (physics of granular matter) and new technology (high-resolution X-ray detection). The work also has important practical applications: poor soil fertility and environmental stress suppress crop yields in many parts of the world, and many models predict abiotic stress will increase in coming decades. Thus, enhanced knowledge of root responses to soil composition and soil moisture could be highly beneficial to agriculture, particularly in developing countries. X-ray CT scans of roots and software necessary for analysis will be made available on repository websites at the Georgia Institute of Technology.

This effort seeks to understand and develop strategies for effective movement in biological and synthetic locomoting systems. Gaits are a fundamental aspect of animal locomotion; examples include a horse's walking, a fish's strokes, and a snake's slithering. In these motions, the animals undergo cyclic motions which interact with the surrounding environment to gain a net displacement over each cycle. The efficacy of such gaits suggests they form a core capability in locomotion of mechanical systems. Understanding the principles of gait-based locomotion offers two opportunities: to gain deep insight into biological processes and to create sophisticated synthetic locomotors to send mechanical systems into dangerous and dirty environments. To gain this insight, questions arise: how to model locomotion, and with this model, how to both evaluate and design gaits to achieve desired locomotive capabilities? In this project, the focus will be on limbless locomotors, including snakes, slender lizards, bacteria, spermatozoa and nematode worms. Limbless locomotor controllers for confined space applications, such as search and rescue in collapsed buildings and landslide debris, will be developed.

The investigators' preliminary work reveals that geometric mechanics allows intuitive understanding of how and why gaits, produce successful locomotion. Much of the prior work with geometric tools, however, provided computationally burdensome approaches to design gaits: choose parameterized basis functions for gaits, simulate the motion of the system and then optimize the input parameters to find gaits that meet the design requirements. Such optimization with forward simulation is computationally expensive. Moreover, existing geometric approaches ignore real world considerations such as body-shape and granular (e.g., dirt) interaction between the mechanism and the environment. Therefore, the intellectual merit of this work is to advance the design and evaluation of gaits for complex systems by representing complex shapes as a basis of curvature functions, while all along empirically deriving from biological observation linear relationships between these parameters and the resulting displacement in granular media. Calculations will then take minutes rather than the days needed for multi-particle discrete element method (DEM) simulation, mitigating the challenges inherent in performing many experiments on real mechanical systems. This work will contribute to a new understanding of biological locomotors as well as help create life-life locomotion in mechanical systems.

We need robots to extend our reach into dirty and dangerous environments. To do so, mobile robots must be able to locomote in messy unstructured terrains. Conventional mobile robots have not begun to display the multi-functionality of organisms that inhabit natural terrains. This is because mobile robots have been created in, and their models mainly validated on, clean hard laboratory floors, whereas biological organisms have evolved to contend with heterogeneous, dirty and unpredictable environments. One important example of such real world complex terrain, often overlooked by our community despite its ubiquity, involves loose granular materials commonly found in deserts, disaster sites, containers, and caves. Therefore creation of the next level of mobility to traverse dirty environments requires simultaneous advances in both robotics and physics, particularly regarding the interactions associated with desired behaviors.

The proposed work is built on a foundation of geometric mechanics, granular physics of intrusion and biological inspiration from desert-dwelling snakes. We use geometric mechanics, a field that applies principles from differential geometry to problems in classical mechanics, to design gaits for biologically inspired robots. We bring the benefits of the geometric tools to bear on granular environments: in even these mathematically "messy" systems, we can begin to efficiently analyze gaits. The key concept in this effort is that systems with complicated, nonlinear low-level physics often exhibit much "cleaner" high-level motion, often approximated by a kinematic relationship. Development of such high-level motion controllers will be aided by our ability to discover basic biological principles of locomotion in granular media. We will therefore develop computationally efficient analysis tools for granular materials and will develop techniques to study the locomotion of systems on the surface of granular media.

The Science and MAth Research Training (SMART) program at Georgia Tech University is contributing well-prepared individuals to the science, technology, engineering, and mathematics (STEM) workforce by providing an educational experience that emphasizes experiential learning. The overall goal of the program is to prepare a cohort of highly talented students, working in science and mathematics to be the technology leaders of tomorrow. It utilizes a Living Learning Community (LLC) with participation of students and faculty from the Schools of Biology, Chemistry & Biochemistry, Biology, Earth & Atmospheric Sciences, Mathematics, and Physics. The program is introducing students to their majors, interdisciplinary and collaborative learning, and research through a series of activities. Specific objectives of the program are to: (i) provide financial assistance to scholars to relieve them of the burden of loans or non-career related jobs; (ii) improve retention of students in the College of Sciences; (iii) decrease the time-to-degree; (iv) increase participation in experiential learning (e.g., undergraduate research, cooperative education, internships, service learning and international study); (v) increase the number of science, technology, engineering, and mathematics (STEM) graduates from underrepresented groups; and (vi) increase the rate at which graduates embark on advanced training or careers in STEM fields. These goals are being achieved by providing scholarship funds to students with financial need, and by developing components to build strong student interactions with research-active faculty members.

The project addresses the challenge of increasing retention of students in STEM disciplines by providing enhanced mentoring and a coherent suite of student support services based around a LLC. This is enhancing the ability of the institution to increase the number of STEM graduates from underrepresented groups to better reflect the composition of the U.S. population. An extensive evaluation programs is designed to quantify the effect of participation in the program, and its individual components, on the academic success of the scholars. Examination of the value of a STEM-based LLC is important as institutions face the challenge of creating programs to recruit and retain STEM majors and enhance interdisciplinary education and training.

Undergraduates are being provided the training and advising necessary to prepare them for an array of research projects and internship experiences. This includes skill-building and professional development seminar classes and monthly lunches. Each year a cohort of 24 students, 8 with S-STEM scholarships and 16 others, enter this program that provides a strong foundation for academic success. A tangible outcome of these interactions is enhanced involvement of scholars in experiential learning programs that provide them with skills, experiences, and motivations so that they are best prepared to succeed at the university and to enter productive, sustainable and rewarding careers. Research opportunities across the university and in collaboration with other on-campus and off-campus units are available, and many faculty members have a culture of publishing with undergraduates as co-authors. The program builds on many successful components of a previous S-STEM program and benefits from synergies with existing student support services and programs.

Major transitions in the history of life occurred when individual biological entities came together to form interdependent groups with emergent properties that differed from the individuals. The most recent of these transitions occurred when solitary organisms joined together to form cooperative societies. This transition to sociality has been particularly remarkable because many distinct individuals are able to behave as a single organism through the coordinated actions of society members. The best examples of such "superorganisms" are colonies of social insects. Social insect super-organisms breathe, feed, grow, breed and modify their environments. Although each life system is important on its own, the balance at the colony level arises from coordinated action of all systems. The purpose of this research program is to discover physical principles that play important roles in super-organism physiology. Super-organism regulatory principles will be of use in systems where information and physical networks coexist, such as in pedestrian and vehicle traffic, urban and disaster landscapes, and neural and artificial networks. The proposed studies could also help explain why the biological transition to sociality has been so successful.

The proposed studies will probe physical aspects of super-organism physiology from a "top-down" approach to discover emergent behavioral, biomechanical, and social features. This will be complemented by a "bottom-up" approach that will discover how aspects of super-organism physiology (exoskeleton, organization of circulatory system, healing mechanisms) depend on soil properties, ant morphology, grain manipulation biomechanics, and genetics. This research will be conducted using the red imported fire ant, Solenopsis invicta, as a model super-organism system. Fire ants possess highly developed social systems and work together to complete complex tasks. The goal of this research is to elucidate principles governing the functioning of the super-organism and the processes responsible for super-organism stability and success. Specifically, this program will study super-organism features that are analogous to those in single organisms including: (1) Super-organism exoskeleton construction: this research will investigate processes by which the super-organism constructs a robust exoskeleton, its nest, from cohesive granular media. Such processes will include biomechanics of excavation in different media, social interactions upon nest formation (like communication, recruitment, workload distribution) and intelligent construction methods (e.g. can ants probe grain level stresses). (2) Super-organism circulation: This research will deduce traffic optimization strategies in confined spaces. Such strategies may include separation of work tasks in space and time, localization of movement in nest space, organization of information hubs, and modification of the carrier's behavior in response to heavy traffic. (3) Super-organism nervous system: This research will discover how information is transmitted through a patterned environment through tactile interactions of individuals. The approaches used will lead to an understanding of how the superorganism nervous and circulatory systems co-exist. (4) Super-organism homeostasis of physical properties of the nest: This research will determine the response of the super-organism to perturbations arising from flooding, mechanical insults to nest networks, invasion of competitive species, and genetic variation derived from hybridization of fire ant species. The research team will leverage the representation of female group members to attract female students to study of the interface between biology and physics, which should attract students who might be discouraged by the barriers in more established fields. The research team will also explore strategies of public involvement through hands-on and DIY initiatives, collaboration with public education clubs and integration of science with the entertainment industry.

DESCRIPTION (provided by applicant): Retinal degenerative diseases often lead to blindness due to lost neurons. A major goal of vision scientists is to restore these lost neurons. Due to their remarkable regenerative powers, zebrafish provide an ideal system for identifying strategies for restoring lost neurons in the retina. Although the zebrafish and mammalian retina are composed of similar cell types that are organized and function in a similar manner, they respond very differently to injury. Zebrafish respond to retinal damage by mounting a regenerative response that restores lost sight, while mammals do not. Key to the success of retina regeneration in zebrafish are Muller glia (MG) that respond to retinal damage by undergoing a reprogramming event that allows them to acquire properties of a stem cell. These reprogrammed MG are responsible for generating a multipotent proliferating population of retinal progenitors that regenerate all major retinal cell types. We propose that an understanding of the mechanisms by which MG reprogram to a retinal stem cell will help identify strategies for stimulating mammalian MG to undergo a similar transformation and repair a damaged retina. This proposal focuses on identifying these mechanisms with an emphasis on secreted factors regulating MG reprogramming and the gene expression programs that drive multipotency. It is anticipated that these studies will lead to novel strategies for inducing MG dedifferentiation and retina regeneration in mammals which may facilitate repairing a damaged or diseased human retina.

Swarm robotics explores how groups of robots can work towards a singular goal. Such a goal is typically achieved by equipping each robot with sensory capabilities, basic computing power, and actuation. The sensors detect something about the environment, this information is used to make a decision about the next action, and some resulting actuation is performed. Swarm robotics has made many advances in recent years, but it is still in its infancy. The PIs will take a "task-oriented" approach and start from a desired macroscopic emergent collective behavior to develop the distributed and stochastic algorithmic underpinnings that the robots will run (at the microscopic level) in order to converge to the desired macroscopic behavior; as part of the process, they will also provide the understanding for yet unexplored collective and emergent systems. The robots envisioned are small in scale, ranging in size from millimeters to centimeters, so that when deployed in crowded (i.e., dense) environments, they will behave as active matter, more specifically as macroscopic programmable active matter. The emergent behaviors of interest for simulations include clustering (forming a tight-knit community that is mostly well-connected), compression (maintaining coherence of a connected community while minimizing perimeter), flocking (determining an agreed upon direction of orientation), and locomotion (collectively moving while maintaining cohesiveness). Many of these have interesting converse problems which are also equally worthwhile, such as exploration (maintaining a connected population, but exploring maximal area) and desegregation (preventing separation in a binary mixture of particles).

The PIs have strong records for interdisciplinary research, including initiating interdisciplinary areas, e.g., robo-physics (Goldman), self-organizing particle systems (Richa), and the fusion of statistical physics and randomized algorithms (Randall). The PIs also have a strong commitment toward supporting minorities, women, and undergraduate research (e.g., through NSF S-STEM programs at ASU; ADVANCE and S.U.R.E. programs at Georgia Tech). This project will bring together techniques from multiple disciplines, and new research approaches and findings will be incorporated into graduate courses. Findings (including open source code) will be published in the various disciplines, and will be made available on the web and ArXiv.

The specific goals of this project are to work toward developing a theoretical framework for task-oriented active matter, informed by models of simple physical systems, that can realize and test the algorithms. The swarm robotics systems that biophysicists build to understand nature can be modified to perform the tasks these new algorithms require. The physical models will allow refinements to the theories under additional constraints, such as gravity and limited energy. It also will allow the PIs to test their algorithms for robustness, as physical systems admit some error. The fundamentals of swarm robotics will be studied from a physics standpoint, by viewing the ensemble as active matter composed of programmable elements at the micro-level. Thus, a (macro-)task oriented approach will be followed in order to design a distributed, stochastic algorithmic framework to construct and evaluate algorithms at the micro-level that yield the targeted emergent macro-behavior.

Blinding eye diseases are among the most feared disabilities afflicting the human population. Macular degeneration and glaucoma are the leading causes of blindness in the USA. These diseases result from neurodegeneration. Although a number of strategies for restoring sight to the blind are being pursued, a regenerative one may be most ideal. Unfortunately mammals do not regenerate their CNS. However, hope comes from zebrafish that posess remarkable regenerative powers and can regenerate a damaged retina. The zebrafish retina shares structure and function with the mammalian retina and therefore, is an ideal system for studying retina regeneration. Key to the success of retina regeneration in zebrafish are Muller glia (MG) that respond to retinal damage by adopting properties of a stem cell that allows them to divide and generate progenitors for retinal repair. It appears that fish MG are more plastic than their mammalian counterparts and this plasticity allows them to acquire a stem cell-like state in response to retinal damage. This plasticity may be influenced by intrinsic mechanisms and also the enviroment MG reside in. Our studies investigates interactions between MG and their environment and how this impacts their quiescence and proliferation. In addition, MG may represent a heterogenous population of which some are more prone to participate in retinal repair than others. Our studies investigate MG heterogeneity and its impact on retina growth and regeneration. Finally, although the ability of zebrafish MG to regenerate neurons is well documented, little is known about the integration and function of these regenerated neurons in the retinal circuitry. Our studies will investigate regenerated neuron integration into preexisting visual circuits and their participation in phototransduction. These studies will not only further our understanding of MG plasticity and neuronal regeneration in zebrafish, but will also suggest new strategies for stimulating retina regeneration in mammals.

Swarm robotics explores how groups of robots can work towards a singular goal, which is typically achieved by equipping each robot with sensory capabilities, basic computing power, and movement. The sensors detect and use information about the environment to decide on the next action. Swarm robotics has made many advances in recent years, but is still in its infancy. This project proposes to explore swarm robotics systems in a non-standard way as physical systems. The PIs take a "task-oriented" approach to develop the distributed algorithmic rules that the robots will run (at the microscopic level) in order to converge to the desired collective behavior (at the macroscopic level). This will provide understanding of the minimal requirements for individuals to accomplish the desired behavior, for both algorithmic and physical realizations, and will provide a more principled approach for studying swarm robotics. The robots envisioned are small in scale, ranging in size from millimeters to centimeters, so that when deployed in dense environments, they will behave as programmable active matter.

The PIs have strong records for interdisciplinary research, including initiating interdisciplinary areas (e.g., robo-physics, self-organizing particle systems, and the fusion of statistical physics and randomized algorithms). They have a strong commitment toward supporting minorities, women, and undergrad research (e.g., through NSF REUs, including through this project, NSF S-STEM programs at ASU; ADVANCE and S.U.R.E. programs at Georgia Tech). Any breakthrough in this combination of swarm and active matter systems will require employing analyses and techniques from stochastic systems, condensed matter physics, swarm systems, robotics, and distributed algorithms to understand and achieve the desired group dynamics, and hence will bring together and educate researchers from different disciplines and specialties. New research approaches and findings will be incorporated into multiple graduate courses and workshops will provide tutorials for bridging multiple disciplines, making material accessible to young researchers and helping to widely disseminate results. Findings (including open source code) will be published in the various disciplines, and will be be made available on our web pages and ArXiv.

The project explores the fundamentals of swarm robotics from a physics standpoint, by viewing the ensemble as active matter composed of programmable elements at the micro-level. The project will follow a (macro-)task oriented approach, and design a distributed stochastic algorithmic framework to design and evaluate algorithms at the micro-level that will yield the targeted emergent macroscopic behavior. The emergent behaviors it addresses include compression (maintaining coherence of a connected community while minimizing perimeter), bridging (connecting two or more locations in the most efficient manner), alignment (determining an agreed upon direction of orientation), jamming (obstruction of movement by increased collective flow), and locomotion (collectively moving while maintaining cohesiveness). Many of these have interesting converse problems which are also equally worthwhile, such as exploration (maintaining a connected population, but exploring maximal area) and non-alignment (representing a disordered ensemble). In some cases the collective behavior acts like a physical system changing between a liquid (disordered) and a solid (ordered) state, as determined by phase transitions in the systems. The project will explore stochastic and distributed algorithms for rigorously achieving these goals.

Summary Blinding eye diseases, like glaucoma, macular degeneration, and retinitis pigmentosa cause neuronal degeneration and lead to severe disability. The restoration of lost neurons using cell transplantation holds promise, but the degenerating retina may prove resistant to exogenous cell integration as it undergoes structural remodeling with disease progression. An alternative approach is to use endogenous stem cells for retinal neuron regeneration. Remarkably, in zebrafish, Müller glia can function as stem cells and regenerate retinal neurons lost to injury or disease. Although Müller glia are found in both the zebrafish and mammalian retina, and share structure and function; only in fish do they regenerate new neurons. Over the past decade, we have learned a lot about the genetic programs and signaling pathways that regulate Müller glia reprogramming and proliferation in zebrafish; however, we still lack an understanding of why they can mount a regenerative response in fish, but not in mammals. It seems likely this information resides in Müller glia?s quiescent state. Interestingly, Notch signaling has recently emerged as an important difference between pro- regenerative Müller glia in the zebrafish retina and non-regenerative Müller glia in the mammalian retina. In zebrafish Müller glia, Notch signaling is active in the basal state and must be suppressed for regeneration to ensue; however, in mice Notch signaling is essentially absent from Müller glia beyond postnatal stages. Interestingly, Notch signaling is also associated with radial glial stem cells in the brain and its suppression is necessary for their cell division and neuronal regeneration. Furthermore, Notch signaling can amplify stochastic events by lateral inhibition and thereby, may drive Müller cell heterogeneity. Zebrafish Müller glia heterogeneity is suggested by differences in gene expression, spontaneous proliferation, and response to retinal injury. In this grant we propose to further characterize Müller glia cell heterogeneity in the uninjured zebrafish retina and connect this heterogeneity to Müller glia?s regenerative potential. In addition, we will investigate how Notch signaling impacts the Müller glia transcriptome to regulate its regenerative properties. It is anticipated that these studies will provide new insights into retina regeneration in zebrafish and lead to new strategies for stimulating Müller glia?s regenerative response in mammals.