Peter Jung - US grants

This award is made under the high performance connections portion of ANIR's "Connections to the Internet" announcement, NSF 98-102. It provides partial support for two years for a DS-3 connection to the vBNS. Applications involve virtual manufacturing and materials processing, on-line EEG data analysis using nonlinear methods, long-term study of TCP/IP (Internet) based applications on high-speed satellite networks; data transfer of nuclear and particle physics research being conducted on an international level between Ohio University and the Thomas Jefferson National Accelerator facility. Collaborating institutions include NASA Lewis Research Center, the Jefferson Lab, and the Children's Medical Center in Cincinnati.

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JUNG

Only a fraction of the cells in brain tissue are neurons. The majority of brain cells are glial cells. The star-shaped astrocytes, a subgroup of glial cells form an integrated network known as a syncytium. Astrocyte syncytia support waves of calcium release that signal information between astrocytes and neurons. The goal of this project is to analyze these signaling patterns in cultures of brain tissue to decipher their messages and to understand how they differ in healthy and epileptic brain cells.
The project will be a collaborative effort between biologists at Viatech-Imaging/Cognetix and physicists at Ohio University. Viatech-Imaging/Cognetix will provide fluorescent video microscopy to observe the calcium waves, and will provide the expertise necessary to grow, modify, and understand the physiology of the cultured brain cells. Ohio University physicists will analyze and model the dynamical properties of the calcium waves to provide a basis for understanding the coherent signaling and communication between regions of cells. The central analytical tool to be used and further developed in this study is called Hyper-cluster analysis. This technique reveals a unique statistical fingerprint of the intercellular messaging. Statistical fingerprints will be obtained in a variety of healthy and epileptic tissues obtained from Children's Medical Hospital in Cincinnati. Once these fingerprints can be deciphered, a wide range of exciting biomedical applications becomes possible. These include personalized quantitative testing of the effectiveness of anti-epileptic compounds and screening of the effectiveness of new drugs in a culture dish without the debilitating side effects that often accompany clinical testing.

The emerging picture of brain function is that of a complex communication network between neurons and astrocytes. It has now become clear that astrocytes - the most numerous types of non-neuronal cells in the brain - are important partners to the neurons. Astrocytes listen to the neuronal chatter, respond to it and talk back to the neurons, thus modulating their functions. Understanding the complex communication network of neurons and astrocytes is therefore significant for the understanding of the brain.
While this emerging field of research has been driven so far predominantly by methods of cellular and molecular biology, the main objective of this project is to add a new set of tools - mathematical and computational modeling - that can offer new avenues to explore the complex neural-glial communication network. A mathematical/computational model - consisting of functional coupled units - generates a unique conceptual framework that allows categorizing biologic processes and generating predictions.

Specifically, this award will enable an exploration of the generation of signals in astrocytes in response to neuronal activity, the spatial spread of the signal through the network of astrocytes, and the effect of the spreading signal back on the neuronal circuit, all significant aspects of interactions between neurons and astrocytes. Realistic mathematical models of these interactions will be developed. After the significant components of the neural-glial communication system are understood, neuronal circuitry with an architecture resembling that in the cortex can be modeled, and the influence of astrocytes on the network will be explored.

These goals will be achieved through the use of modern imaging tools employed in a cell biologist's laboratory, from which critical data on intracellular calcium signaling will be used to develop realistic mathematical modeling of the neural-glial interactions.

This project has significance far beyond the specific purpose of understanding the communication network of astrocytes and neurons in the central nervous system. Quantitative and conceptual understanding of neural-glial interactions may provide a basis for a better understanding of brain disorders such as migraine and epilepsy, in which a glial component is strongly suspected. Additionally, understanding of the intracellular calcium signaling, an important signaling pathway between astrocytes, is of critical importance for signaling in a variety of tissues, such as liver, where it contributes to the release of enzymes, and in corneal and bronchial epithelia where it is involved with wound response.

Nerve cells communicate by conducting electrical signals along slender cytoplasmic extensions known as axons. Animals have evolved two basic mechanisms for increasing axonal conduction velocity. One is to increase axonal diameter and the other is to insulate axons by a process called myelination, which is a tight spiral wrapping of the axons that is formed by myelinating cells. In vertebrates the growth of axon diameter is caused principally by the accumulation of space-filling cytoskeletal polymers called neurofilaments inside the axons, and this is regulated locally by chemical signals from the myelinating cells. It is known that neurofilaments are transported along axons and that they alternate between rapid movements and prolonged pauses. The proportion of the time that the neurofilaments spend pausing is likely to be a principal determinant of their residence time in axons. This is a collaborative experimental and modeling project involving a biologist at Ohio State University and a physicist at Ohio University. The central hypothesis to be tested is that myelinating cells control axonal caliber by regulating neurofilament pausing. A computational model will be developed that relates the moving and pausing behavior of neurofilaments to their distribution along axons. The model will be based on detailed kinetic parameters of neurofilament movement derived experimentally in cultured neurons and will be verified experimentally by fluorescence microscopy of neurofilament movement in myelinated axons in tissue culture. The proposed research will generate a rigorous and quantitative framework that relates the size and shape of axons, which is a key influence on their electrical properties, to the moving and pausing behavior of their internal constituents. The research will involve graduate and undergraduate students in both the physical and biological sciences, providing an integrated and cross-disciplinary training experience at the interface between computational and experimental biology.

Peter Jung and Khaled Machaca
Proposals IOS-0744798 and -0744581
Collaborative: Modeling of Calcium Signaling differentiation during Oocyte maturation

A unique opportunity to offer novel approaches toward the understanding of developmental aspects of one of the most important cellular signaling systems, calcium signaling, has developed from the interaction between a computational biological physics laboratory and a cell biology laboratory. The notion of a calcium signal refers to a transient increase of free cytosolic calcium ions. Ca2+ signals span a wide range of spatial and temporal scales, which endow them with the specificity required to induce defined cellular functions. For example, localized Ca2+ release through ryanodine receptors in vascular smooth muscle leads to relaxation, whereas global sustained Ca2+ signals lead to contraction. The molecular mechanisms, however, by which signaling specificity is achieved during development remain poorly understood. While this field of research has been driven so far predominantly by methods of cellular and molecular biology, this project will add a new set of tools - mathematical and computational modeling from the nanometer to the millimeter scale - that can offer new venues to explore changes in the complex intracellular Ca2+ signaling network during development. In terms of scientific Broader Impacts, the results from this work will have implications for a large variety of cell types since calcium signals are ubiquitous and regulate a plethora of cellular functions including neurotransmitter release, contraction of smooth muscle cells and fertilization.

The educational Broader Impacts of this proejct are enhanced by the interdisciplinary nature of the work. The project will foster interdisciplinary training of undergraduates, graduate students and postdocs. Trainees at different levels of their career from two different institutions, will acquire expertise in both mathematical and experimental approaches.

Nerve cells communicate by sending electrical impulses along thin protrusions called axons. One mechanism by which animals increase velocity of electrical impulses is to expand axons' cross-sectional area. This expansion is caused by an accumulation of microscopic space-filling protein polymers called neurofilaments, which are transported into axons where they form a dynamic scaffold. This collaborative project will use microscopic imaging in conjunction with computational modeling to test the hypothesis that neurofilament accumulation in axons is caused by a slowing of neurofilament transport, much as cars pile up on highways when the traffic slows. This project will provide a rigorous and quantitative framework that relates the size and shape of axons, which is a key influence on their electrical properties, to the motile behavior of their internal constituents. This work will also shed light on the mechanism by which neurofilaments accumulate abnormally and excessively within axons in many neurodegenerative diseases.

This project will provide a unique training opportunity at the interface of computational and experimental biology for students with diverse backgrounds in the physical and life sciences. An emphasis will be placed on mentoring undergraduates lacking prior research experience, including women and minorities, through annual Research Experiences for Undergraduates fellowships. The investigators will also reach out to undergraduates by participating together in the Research for Undergraduates: Adventures in Mathematical Biology and its Applications curriculum at Ohio State University, which is an NSF-funded Undergraduate Biology and Mathematics program, and by serving as joint mentors in the Undergraduate Summer Research Program of the NSF-funded Mathematical Biosciences Institute at Ohio State University. Lastly, a neurofilament wiki page will be developed featuring information and resources on mathematical modeling of axonal transport to support these outreach activities and to facilitate the exchange of data between the two laboratories.

Nerve cells extend long, thin protrusions called axons that define the wiring pattern of the nervous system. Axons allow nerve cells to communicate electrically with each other and with other cells throughout the body. Each axon contains a microscopic, internal scaffold of space-filling proteins called neurofilaments that are constantly shuttled along the axon by molecular motor proteins; these define axon shape and size. Neurofilaments accumulate during development, increasing axon diameter and allowing electrical activity to travel more quickly; excessive accumulation (as occurs in many neurodegenerative diseases) can lead to communication abnormalities and axonal degeneration. This project tests the hypothesis that the rate of neurofilament transport determines the diameter, shape and function of axons. The work will be conducted by a seasoned interdisciplinary team of biologists and physicists, combining innovative biological imaging techniques with mathematical and computational methods to investigate these important questions. The insights gained from this research will be critical for understanding healthy brain function and could also provide important insights into the axonal problems observed in many neurodegenerative diseases. Trainees on this project from both the physical and life sciences will work in teams supervised by the principal investigators, and will expand their skills through interdisciplinary interaction, adding to the skilled research workforce at the interface of the physical and life sciences. To extend the impact of the proposed research to the K-12 level, the physicists and biologists on this project will host focused, small-group workshops that will seek to empower middle and high school teachers with ideas and tools to invigorate their instruction in the areas of cell biology and algorithmic thinking, and introducing freely available but powerful learning tools that they can apply in their classrooms.

The function of nervous systems is dependent on the propagation of action potentials along axons at a velocity that is specific to their physiological function. This velocity is dependent on axon size and shape. A principal determinant of axon size and shape in vertebrates are space-filling cytoskeletal polymers called neurofilaments. Neurofilaments are also cargoes of axonal transport that move along microtubule tracks. Thus, neurofilaments define axonal morphology, but they are also in constant flux. The proposed research addresses this intriguing and physiologically important relationship. The central hypothesis is that the kinetics of neurofilament transport determines axonal neurofilament content, which in turn specifies axonal caliber and function. The specific goals are to determine the dynamic interplay between neurofilament transport velocity and flux in the specification of overall axon caliber, and how neurofilaments navigate local constrictions at the nodes of Ranvier. To accomplish these goals, the investigators will employ a tight integration of computational and mathematical methods with innovative live imaging of myelinated axons in peripheral nerves ex vivo from a new transgenic mouse that expresses a photoactivatable neurofilament protein in neurons.