2009 — 2012 |
Pralle, Arnd Berry, James |
N/AActivity Code Description: No activity code was retrieved: click on the grant title for more information |
Mri: Acquisition of a Confocal Microscopy System For Research and Education
This Major Research Instrumentation (MRI) award funds the acquisition of a state-of-the-art confocal microscope to enhance research and education at the University at Buffalo (UB). This multifunctional instrument meets the needs of a diverse interdisciplinary user group on the University of Buffalo North Campus, where accessibility to confocal imaging is lacking. Users include faculty within Departments of Biological Sciences, Physics, and Chemical and Biological Engineering. Research ranges from cell and nuclear organization, developmental biology, neurobiology, stem cells, tissue engineering, plant biology, and molecular evolution, in organisms ranging from animals, plants, fungi, nematodes, insects, and arthropods. Some users require basic confocal applications, while others require advanced features. The instrument that meets these diverse needs is a motorized inverted Nikon A1R Confocal Microscope, which combines precision point and ultra-fast resonant scanning, together with Nikon's exclusive Perfect Focus. An environmental chamber will enable long-term live cell imaging. A complete set of lasers allows imaging of a full range of fluorescent molecules, FRET, and photo-activatible GFP. An integrated Becker-Hickl FLIM module allows for FLIM FRET, and a unique Fianium supercontinuum SC400 laser maximizes versatility by covering the entire 400 nm to 2000 nm spectrum. This microscope will be accessible to faculty, postdocs, and students in a variety of scientific disciplines, and will be a central component of new courses and workshops. Additionally, the primary investigators will work with University of Buffalo-based outreach programs to promulgate accessibility of associated courses, training, seminars, and workshops to underrepresented groups within our academic populations, providing research and education tools that would otherwise be unavailable.
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0.946 |
2011 — 2014 |
Pralle, Arnd |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Deep Tissue Magneto-Genetic Cell-Stimulation For Neuroscience and Therapy @ State University of New York At Buffalo
DESCRIPTION (provided by applicant): One major goal of neuroscience is to unravel the neural circuitry and processing that control animal behaviors. A greater understanding of these systems can help in the treatment of diseases which are currently alleviated using invasive deep brain stimulation. Hence, methods for non-invasive, remote control of neuronal activity are at the top of the wish list for many neuroscientists. The goal is to develop a method to stimulate specific subsets of neurons deep in the brain without requiring a physical connection to the outside world. The objective of this proposal is to demonstrate that alternating magnetic fields may be used to stimulate neurons deep inside mammalian brains by using nanoparticles to convert the magnetic field energy into localized heat and genetically expressing a temperature sensitive ion-channel which then converts the heat stimulus into membrane depolarization. Magnetic fields interact only weakly with tissue, making them well suited for deep tissue stimulation. The fields and frequencies used will be comparable to those used in standard MRI machines. The approach contains several extremely innovative and novel concepts: (1) magnetic neuro- stimulation, (2) conversion of magnetic fields into heat to create a local and biologically detectable stimulus, (3) targeting nanoparticles to the cell membrane to achieve sub-cellular localization of the heating, and (4) genetic engineering of neurons to synthesize magnetic nanoparticles are all novel and innovative ideas. The proposed research is highly significant because it provides a method by which the relationship of neuronal circuits to animal behavior can be studied. This capability will (i) increase our understanding of normal and pathological brain function, and (ii) provide new therapeutic avenues for remote stimulations in conditions with reduced natural stimulations, such as traumatic brain injuries, Parkinson's disease, dystonia or major depression. PUBLIC HEALTH RELEVANCE: The proposed EUREKA research is relevant to public health because a remote neuro- stimulation method will allow neuroscientists to gather the knowledge of how specific neuronal circuitry governs animal and human behavior. The results of the proposed research are expected to lead to improved treatments of ailments benefiting of specific stimulation of specific neurons or group of neurons, such as traumatic brain injuries, Parkinson's disease, and dystonia or major depression, as well as peripheral paralysis. Thus the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help to protect and improve mental health.
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1 |
2012 — 2013 |
Pralle, Arnd |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Membrane Biophysics of Enterotoxin Mediated Immunomodulation @ State University of New York At Buffalo
DESCRIPTION (provided by applicant): There is a fundamental gap in our understanding of how Enterotoxin LT-II binding to angliosides in the cell membrane modulates the structure and function (e.g. membrane-associated signaling) of the immune-cell membrane. It is necessary to address this gap in order to understand and further the use of these molecules as adjuvants to potentiate the cellular immune response. Such adjuvant reagents are essential components of vaccines. Our long-term goal is to understand the impact of changes in cell membrane ultra-structure on immune-cell membrane signaling at the molecular level. The objective of this proposal is to determine how the adjuvant Enterotoxin LT-II alters the membrane ultra-structure to influence membrane signaling. In particular, we aim to determine the effects of Enterotoxin binding on interactions between membrane proteins and cholesterol-dependent and -independent membrane domains, or nanoclusters. Based on preliminary data, our hypothesis is that adjuvant binding to gangliosides increases the stability of cholesterol-dependent nanoclusters, or the association of the receptor proteins with these clusters. The rationale for the proposed research is that a biophysical model of the influence of changes in membrane ultra-structure on cellular signaling will explain adjuvant potentiation of immune signaling. This hypothesis will be tested by quantifying the effects of Enterotoxin on the size, stability, and association of immune signaling proteins with lipid- and protein-membrane domains, and the membrane cytoskeleton; and by indentifying which membrane bound immune signaling processes are influenced by Enterotoxin binding. Our approach is extremely innovative and novel: We will establish advanced imaging methods which allow us to quantify membrane protein interaction with cholesterol-dependent and -independent nanoclusters and cytoskeleton continuously in intact cells. Our methods will enable a first real-time quantification of membrane structure modulation induced by enterotoxin binding. In addition, our study is uniquely suited to identify the relationship of changes in membrane structure to modulation of membrane function, e.g. cell signaling. By establishing this direct association between structural and functional changes in response to external perturbation will achieve an understanding of the role of the structure for function. The proposed research is significant because it will enhance our basic molecular understanding of the effect of enterotoxin like adjuvants, thus facilitating further investigation into optimizing the desired immune potentiating function. In addition, our results will expand the current understanding of the regulation of membrane structures such as lipid domains and the membrane cytoskeleton, and will elucidate their roles in natural immune function. PUBLIC HEALTH RELEVANCE: Experiments to reveal the molecular processes by which enterotoxin-like agents modulate membrane ultra-structure and the mechanisms by which these changes influence immune signaling will guide the design of future immune adjuvants, which will have direct relevance to issues of public health. The broader impact of this project will be an improved understanding of how agents that modulate membrane structure influence cell signaling. Thus, the proposed research is relevant to NIH's mission that pertains to developing fundamental knowledge to help to protect and improve human health.
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1 |
2016 — 2019 |
Anikeeva, Polina O [⬀] Pralle, Arnd |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Multi-Site Non-Invasive Magnetothermal Excitation and Inhibition of Deep Brain Structures @ Massachusetts Institute of Technology
Abstract This project seeks to develop a wireless, minimally invasive bi-directional deep brain stimulation technology based on remote heating of magnetic nanoparticles. Reliably modulating the activity of specific neuronal populations is essential to establishing causal links between neural firing patterns and observed behaviors. Electrical stimulation, as well as its recent non-invasive alternatives, ultrasound and electromagnetic induction, do not discriminate between cell types and have limited spatial resolution. Genetic approaches such as DREADDs and optogenetics enable neural excitation and inhibition with exquisite precision in specific cell populations. However, they require long-term indwelling hardware (limiting clinical translation) or lack temporal resolution. In this project, we propose to evaluate a nanoparticle-based technology that can access the deep brain regions, excite and inhibit neurons, and be fully wireless after initial injection. The Anikeeva (MIT) and Pralle (SUNY Buffalo) groups have recently shown that heat dissipation by magnetic nanoparticles (MNPs) in alternating magnetic fields (AMFs) can trigger heat-sensitive capsaicin receptor TRPV1 and heat-sensitive chloride channel anoctamine 1 (ANO1), respectively. These, in turn, can depolarize or silence neurons, and we have preliminary evidence for effects both in vitro and in vivo. Finally, the Anikeeva group has made advances in nanomaterials chemistry that enables multiplexing: independent heating of multiple MNP types (implying control of multiple neighboring neural populations) using AMF with distinct amplitudes and frequencies. Our objective is to combine these technologies into a magnetothermal toolbox and demonstrate its ability to shape animal behavior, by manipulating a well-characterized midbrain reward circuit. We will refine the ANO1 inhibitory technology and demonstrate control of place aversion in mice (Aim 1), then merge this technology with TRPV1-facilitated excitation in context of magnetic multiplexing to show bi-directional control of place aversion/preference (Aim 2). From this proof of concept, Aim 3 seeks to demonstrate that the toolkit can also control a more complex behavior (gambling/ probabilistic reward learning) in a larger species (rat). We will carry out this project through a tightly integrated combination of expertise in nanoscale engineering (Anikeeva, Pralle), targeted neural modulation (Anikeeva, Pralle), behavior manipulation through midbrain modulation (Widge) and clinical psychiatric deep brain stimulation (Widge).
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0.907 |