Recipient   Princeton University City   Princeton, NJ Description   The goal of this proposal is to elucidate the behavior of active matter at length scales ranging from microscopic to macroscopic, using an interdisciplinary approach involving both physics and biology. The materials unifying all of the experiments are filamentous microtubules and molecular motors (such as kinesins) that use ATP hydrolysis to propel themselves along the microtubule tracks and thus drive the assembly toward non-equilibrium active states. The project will specifically develop three model systems of active matter. First, a "bottom up" approach will be used to determine the minimal system, consisting of microtubules, active motors and passive cross-linkers, required to create a self-oscillating active bundle. Second, a complementary "top down" approach will be used to deconstruct a fully functional axoneme and determine the minimal set of structural components required for its active beating. This effort will involve a combination of genetic, ultra-structural and biophysical methods. Third, active nematic liquid crystals will be assembled and characterized both for microscopic dynamics and behavior at continuum length scales. (Amount Awarded:$1,000,000) William Bialek Recipient   University of California, Berkeley City   Berkeley, CA Description   Why do embryos form limbs while postnatal humans form scar tissue? This fundamental question remains elusive under existing medical-research paradigms. Current knowledge of amphibian limb regeneration cannot explain the lack of functional tissue re-growth in adult mammals. Although limb regeneration via blastema has been observed in neonatal mice, little is known in cellular or molecular terms. Consequently, controlling and enhancing postnatal organogenesis for therapeutic ends appears to be an intractable challenge. Thus, the researchers seek to transform present understanding of the dramatic decline in regenerative capacity after birth by inventing technology capable of probing cellular and molecular determinants of regeneration in single mammalian cells. Their combined efforts will develop: 1) a novel cell-sorting tool to isolate from tiny tissue clusters the single cells that are pivotal to mammalian tissue regeneration; 2) new tools to study molecular mechanisms orchestrating the regenerative behavior at single cell levels; and 3) 3D ex-vivo systems to recreate the regenerative processes biosynthetically, thereby identifying molecular cues driving tissue regeneration. This single-cell approach may surmount prevailing limitations, thus advancing the frontiers of biomedicine and engineering. (Amount Awarded:$1,000,000) Lydia Sohn Recipient   University of California, San Diego City   La Jolla, CA Description   Demonstrating that there is a fundamental, unifying principle for the operation of biological networks, one that cuts across phylogeny and type of network, could revolutionize the natural sciences. This project will use a research strategy based on the concept of relational networks, in which the coordinated interactions among functional sectors of the network are more critical than the specific identities of any of the interacting components. The program combines experimental network perturbation and global monitoring in genetic and neuronal model systems, followed by theory development, going beyond the standard computational modeling to capture the essential, relational nature of the system at a higher level. Should there prove to be fundamental, universal principles underlying the relations and function of biological networks, they will have substantial implications not only for many areas of biology, including the prospects for synthetic cells and therapeutic developments, but also for the design and implementation of artificial networks in applications as diverse as computing, engineered devices, and communications. (Amount Awarded:$1,000,000) Ralph J. Greenspan Recipient   University of California, San Francisco City   San Francisco, CA Description   Among the greatest achievements of modern medicine is the development of vaccines, but for many important diseases, such as HIV, tuberculosis, and malaria, the production of safe and effective vaccines have been elusive. This is especially true for malaria, a disease that disproportionally affects children. An important first step in developing a rationally designed synthetic vaccine is the identification of antigens and their epitopes that are the actual determinants of immunological protection. The investigators propose to develop a new platform for the production of programmable proteome-scale peptide arrays on beads using a novel approach, whereby millions of peptides can be made deterministically and inexpensively on spectrally encoded microbeads. They will then conduct immunoassays on these beads to map epitopes across the entire proteome, using rodent malaria as a model system. The overall goal is to correlate mapped epitopes with actual protection from disease to inform the vaccine design process. This proposal embodies several major technological and conceptual innovations, and beyond vaccine design, this approach has the potential for broad impact on many fields of biomedical research, including cancer diagnostics, autoimmunity, and allergy. (Amount Awarded:$1,000,000) Joseph DeRisi Recipient   Buck Institute City   Novato, CA Description   Scientists at the Buck Institute share a common goal: to understand aging. We have recently made key discoveries that point to a deep mechanistic relationship between disease and aging across diverse species and various age-related diseases. Our collective data suggest that, rather than viewing aging as a risk factor, it may be more accurately viewed as a principal causal factor of these disorders. We propose to test the hypothesis that age-related human disease is the result of segmentally-accelerated aging--in other words, that diseases of aging such as Alzheimer's disease, prostate cancer, and osteoporosis are part and parcel of the fundamental aging process itself, simply enhanced in the affected tissues. This is based in part on our recent discovery of an acceleration of the aging process in terms of oxidative modification to mitochondrial complex I (CI) in affected regions of the Parkinsonian versus the normal aging brain; selective inhibition of this enzyme complex has been long associated with Parkinson’s disease (PD). To test our hypothesis, we propose two experimental programs: (1) to undertake a functional analysis of mitochondrial post-translational modifications (PTMs) particularly in CI to determine which are critical for neuronal cell dysfunction, death and progression of PD; and (2) to test the generality of this mechanism by surveying Alzheimer's disease models and post-mortem patient brain tissues for mitochondrial PTMs and their functional correlates particularly but not limited to mitochondrial complex IV whose inhibition has been suggested to be preferentially involved in this age-related disorder versus changes associated with normal aging. (Amount Awarded:$1,500,000) Recipient   J. David Gladstone Institutes City   San Francisco, CA Description   The ability to control one’s movements is essential to life. Neural circuits involving the basal ganglia are critical for proper motor control, and disruption of these circuits leads to movement disorders such as Parkinson’s disease and Huntington’s disease. The striatum, which is the input nucleus of the basal ganglia, is a major site of activity-dependent plasticity in both health and disease. Because the striatum lies upstream of other basal ganglia nuclei, cellular and synaptic plasticity within this region alters the transfer of information throughout basal ganglia circuits. However, studies of the striatum have been hampered by difficulties identifying different types of cells during both in vitro and in vivo experiments. Here, we propose to utilize recently developed optical and genetic technologies to characterize the properties of striatal neurons and the neural circuits in which they are embedded. In vivo fiber optic technology will be used in conjunction with expression of channelrhodopsin and halorhodopsin to identify and directly drive neural activity in striatal neurons of awake behaving mice. These experiments will allow us to address how the rate and timing of activity in basal ganglia circuits are causally related to motor behavior. The ultimate goal is to develop a framework that will enable the rational design of novel therapies for devastating disorders affecting the striatum. (Amount Awarded: $1,500,000) Recipient   Northwestern University City   Evanston, IL Description   Little is known about the signaling networks that support the integration of the male and female germ cells into a new totipotent cell, the one-cell embryo. We propose that heretofore poorly understood inorganic signaling molecules initiate the massive changes in the physiology of a fertilized egg. Based on preliminary studies, the team hypothesizes that fluxes in zinc ions mediate the first definitive signal in embryonic development. This hypothesis will be tested by two approaches: one targets real time changes in the subcellular concentrations of free zinc and calcium in live cells and the other rigorously maps specific changes in the total zinc pools at the nanometer level. The mouse oocyte is an ideal model system to study this novel inorganic signaling pathway. It undergoes a clear developmental pattern of receptor-mediated events as it transitions from a dormant stage to a fully active state upon fertilization. Also, its large size facilitates spatial localization of key molecular players. New analytical tools will be developed to map the abundance of specific inorganic molecules and biological receptors. (Amount Awarded:$1,600,000) Recipient   Stanford University City   Stanford, CA Description   Excitable cells are the biological building blocks of brain, heart, and muscle, and communicate and compute using tiny, transient electrical currents. Widespread throughout the body, these cells underlie remarkable behaviors, from orchestration of movement to high-level cognition. When they malfunction, these cells give rise to devastating diseases, ranging from heart failure to Parkinson's disease to depression; however, the interventional tools currently available to deal with these conditions are exceedingly primitive, have severe side effects, and yield little or no understanding of healthy cells or of disease processes. New technology is required, powerful enough to address the high speed and structural complexity of these electrical tissues. This grant is for a four-year project to address this fundamental obstacle by developing and applying emerging optical technologies first developed at Stanford. This light-based bioengineering approach has the power to control cellular functioning in vivo with millisecond precision, and to control intracellular messengers in specific cell types, thereby opening new vistas of both investigation and healing. The project personnel will develop the science and technology of this approach and apply these tools for the first time to mammalian models of neurological, neuropsychiatric and cardiac disease, spanning the central, peripheral, and autonomic nervous systems. (Amount Awarded:$1,500,000) Recipient   University of Colorado at Boulder City   Boulder, CO Description   This proposal requests support to develop innovative research strategies in mass spectrometry in order to detect and characterize all proteins in a cellular "proteome" (i.e. all proteins present in a single cell type). Mass spectrometry is the most powerful tool for addressing this problem and worldwide efforts are underway to define the proteomes of organisms, tissues and fluids. However, such efforts are stymied by the inability to comprehensively observe all proteins in highly complex biological samples. The goal is to create innovative experimental and computational technologies that will enhance the accuracy and sensitivity of protein detection by mass spectrometry, and enable comprehensive protein identification. In order to expand the depth to which the proteome can be observed, funds will be used to purchase a high resolution mass spectrometry system with capabilities for electron transfer dissociation. With this instrument, new methods will be developed to overcome limitations in data collection and solve major hurdles in recovering information from large scale datasets. These will be applied to collaborative research efforts between eight laboratories, providing the possibility for unprecedented capabilities to answer questions that were previously impossible to address. (Amount Awarded: $1,200,000) Recipient   City of Hope City   Los Angeles, CA Description   To continue work to understand the molecular mechanisms underlying cancer and develop therapies that destroy lymphoma cells without harming normal cells. Recipient   Arizona State University City   Tempe, AZ Description   To study frameshift peptides common in tumors as targets for development of a cancer vaccine. Recipient   Carnegie Mellon University City   Pittsburgh, PA Description   To research how the brain composes neural representations of word and sentence meanings from their component parts. Recipient   Stanford University City   Stanford, CA Description   To develop equipment to study the structure and dynamics of neural circuits. Recipient   Translational Genomics Research Institute City   Phoenix, AZ Description   To develop network models of biological function using signal processing and control theory. Recipient   University of California, Los Angeles City   Los Angeles, CA Description   To develop stem cell technology to engineer human immune cells for targeted cancer treatments. Recipient   University of California, San Francisco City   San Francisco, CA Description   To characterize and understand the function of the non-protein coding RNA genes by developing new mouse models for human disease. Recipient   University of Massachusetts Medical School City   Worcester, MA Description   To study how asymmetric cell division affects aging and longevity in somatic and stem cells. Recipient   University of Oregon City   Eugene, OR Description   To study biological interactions of engineered nanoparticles and establish fundamental design rules for biomedical applications. Recipient   University of Texas - M. D. Anderson Cancer Center City   Houston, TX Description   To understand molecular mechanisms behind the generation of immunosuppressive T-cells in the thymus and tumor microenvironment and to develop cancer immunotherapies. Recipient   City of Hope City   Los Angeles, CA Description   To understand the molecular mechanisms underlying cancer and develop new therapies that destroy lymphoma cells without harming normal cells. Recipient   Cold Spring Harbor Laboratory City   Cold Spring Harbor, NY Description   To map the architecture of the human and rodent brain and gain an insight into neural dynamics underlying motivated behavior. Recipient   Indiana University-Purdue University Indianapolis City   Indianapolis, IN Description   To understand the mechanisms of regeneration and restoration in amphibians and apply these mechanisms in potential therapies for spinal cord injury patients. Recipient   Mount Sinai School of Medicine City   New York, NY Description   To study the pandemic risk of avian influenza viruses using an animal model of human transmission. Recipient   University of California, Berkeley City   Berkeley, CA Description   To establish a laboratory to research structures and functions of the fundamental molecular machines that mediate information flow in cells and viruses. Recipient   University of Louisville City   Louisville, KY Description   To study the cellular and molecular mechanisms of facilitating-cell regulatory function on hematopoetic stem cells. Recipient   University of Michigan City   Ann Arbor, MI Description   To develop an integrated system of distributed microscale actuators, intracellular sensors and feedback controls capable of chemically interfacing with a developing embryo. Recipient   University of Pennsylvania City   Philadelphia, PA Description   To develop novel methods for understanding the cell types involved in neurodegenerative diseases like Parkinson's, and develop therapeutic interventions. Recipient   Washington State University City   Pullman, WA Description   To gain insight into the mechanisms underlying the phenomenon of sleep. Recipient   Yale University City   New Haven, CT Description   To map basic cellular networks in the brain and the immune system. Recipient   Dana-Farber Cancer Institute City   Boston, MA Description   To support the Human Interactome Project, which will provide insight into the networks of physical interactions among cellular proteins. Recipient   Oregon Health & Science University City   Portland, OR Description   To equip the Advanced Imaging Research Center with a 11.75T animal MR imaging and spectroscopy system and develop high-resolution, high-sensitivity brain imaging methodologies. Recipient   Oregon State University City   Corvallis, OR Description   To build an electron capture dissociation chamber to improve fragmentation of peptides and therefore data obtained from mass spectrometry. Recipient   Tufts University City   Medford, MA Description   To purchase instrumentation required for the study of complex interrelationships between the human immune system and its disease-causing pathogens. Recipient   University of California, San Diego City   La Jolla, CA Description   For a tri-institutional collaboration to analyze human stem cell differentiation pathways using extremely rapid robotic screening techniques. Recipient   University of California, Santa Barbara City   Santa Barbara, CA Description   To define the role of specific microRNAs in the establishment and maintenance of neuronal identity. Recipient   University of New Mexico City   Albuquerque, NM Description   To study a newly identified class of steroid receptors that are highly expressed in tumors, which will advance the development of new and more effective cancer treatments. Recipient   Doheny Eye Institute City   Los Angeles, CA Description   To support the intraocular retinal prosthesis program. Recipient   George Washington University City   Washington, DC Description   To combine a MALDI mass spectrometer with a scanning near-field optical microscope to obtain images of protein distribution in living cells and tissues. Recipient   Jackson Laboratory City   Bar Harbor, ME Description   For research into gene function and expression at the cellular and subcellular levels using a new generation of confocal microscopy techniques. Recipient   Memorial Sloan-Kettering Cancer Center City   New York, NY Description   To explore the molecular and cellular mechanisms of cancer metastasis using imaging methods and molecular biology techniques. Recipient   Tulane University City   New Orleans, LA Description   To develop adult stem cells for research use, and specifically to study the molecular mechanisms used by stem cells to repair tissue damage. Recipient   University of Wisconsin, Madison City   Madison, WI Description   To study the biological mechanisms that cause undifferentiated embryonic stem cells to develop into cells with highly specific functions. Recipient   Washington University in St. Louis City   St. Louis, MO Description   To explore how the microbial community that inhabits the gut influences nutrition, immunity, cancer risks and other aspects of human health. Science & Engineering Research Medical Research Undergraduate Education Southern California Program