Wei R. Chen - US grants

[unreadable] DESCRIPTION (provided by applicant): The mammalian olfactory system has a tremendous capability to discriminate thousands of different odor molecules. Recent advances in molecular biology and functional imaging have established that odor information is encoded as spatial patterns of activated glomeruli distributed on the olfactory bulb surface. How these glomerular coding patterns are transformed within the olfactory bulb circuits is critical to odor discrimination and recognition, but remains to be understood. As a unique feature of olfactory bulb neuronal circuits, most of the cell-cell communication is mediated by synapses and gap junctions made between dendrites of principal mitral/tufted cell and local interneurons. Our previous research has established how signals encoding odor information are transmitted and regulated dynamically along the mitral cell primary and secondary dendrites. The aim of this renewal application is to continue this line of research by combining patch-clamp recording, two-photon calcium imaging and green fluorescence protein-targeted transgenic/knock-in mice to analyze how the bulbar neurons interact with each other at a level of circuits to process glomerulus-specific odor information. Specifically, we will test three major hypotheses. First, one important function ofperiglomerular cells is to orchestrate the glomerulus-specific firing synchrony through both dendritic synaptic transmission and electrical coupling in the glomerulus. Second, neuronal activities within different glomeruli can also achieve temporary synchrony, and both periglomerular and granule cells play a important role. Third, signal transmission in granule cell dendrites and spines has a spatio-temporal dynamics that can mediate the coupling and uncoupling of mitral cells from different glomeruli as in response to different odorants. These experiments are in line with our long-term objective to obtain critical information on the functional principles of olfactory bulb dendritic circuits and how these principles are involved in odor signal processing and discrimination. The progress toward this objective will yield novel insights into how the olfactory system can recognize thousands of different odors, and into the neural basis of smell-related disorders. [unreadable] [unreadable]

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[unreadable] DESCRIPTION (provided by applicant): The long-term goal of this research is to understand how the olfactory system encodes odor information, and how olfactory sensory codes are transformed sequentially through different processing stages along the central projection pathways. Olfactory coding and processing have been extensively studied with two major approaches: (1) electrophysiology of single neurons, which can record neural activity at any tissue depth, but blindly without knowing network context in reference to upstream coding patterns; and (2) CCD camera imaging of spatiotemporal pattern of activated glomeruli, which is ideal for revealing the initial glomerulus-based codes, but lacks single-cell resolution and deep penetration required for exploring odor codes beyond the glomerular layer. This grant is aimed at bridging such a gap between single-cell physiology and large-scale CCD camera imaging, so as to unify the two large datasets already available in the literature. First, using a new transgenic mouse model, we will provide a direct comparison between the pre- and postsynaptic odor maps within the glomerular layer, and test the hypothesis that lateral circuits intrinsic to this layer can support interglomerular lateral inhibition and/or excitation for initial odor-map transformation. Second, by combining in vivo two-photon calcium imaging and targeted single-glomerulus dye labeling, we will perform a systematic analysis of odor ensemble codes carried by the mitral/tufted cells associated with a common glomerulus. We will test the hypothesis that both the overall size and distribution pattern of a glomerulus-defined active cell ensemble can be effective coding factors for odor intensity at least and maybe also identity. Finally, by imaging the mitral cell population with diverse glomerular projections, we will analyze the cross-glomerular odor ensemble responses in the context of corresponding glomerular activation patterns. We will study how the glomerulus-based odor codes break down into distributed mitral-cell population codes, and ask what is the benefit of redistributing odor signals which have just converged via the nose-to-bulb projection. Collectively, these studies should not only have a significant impact on our understanding of the neural basis of odor processing and discrimination, but could also yield novel and more general principles on how the brain transforms neural codes for achieving sensory and perceptive functions. PUBLIC HEALTH RELEVANCE The sense of smell plays an important role in our daily life style involving flavor and fragrance appreciation. Dysfunction of the olfactory system happens in many human diseases such as eating-related obesity and early development of Alzheimer's disease. The general goal of this grant in understanding the neural basis of odor coding and processing will not only help the diagnosis and treatment of these diseases, but will also promote people's life quality in general. [unreadable] [unreadable] [unreadable]

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term objective of this project is to develop a novel method, photoimmunotherapy, combining biophotonics and nanotechnology, for treatment of metastatic tumors, using magnetic resonance thermometry (MRT) guidance for its selective photothermal interaction. The Pis have developed laser immunotherapy using a near-infrared laser, indocyanine green (ICG, a chemical dye), and glycated chitosan (GC, a polymer) for treatment of metastatic tumors. Recently, the Pis discovered that GC was an excellent surfactant for single-walled carbon nanotubes (SWNTs), which can strongly absorb light of 980-nm wavelength, to which biological tissue is almost transparent. It is hypothesized that GC-SWNT, when administered to the target tissue and activated by laser light of appropriate wavelength, could induce selective photothermal and immunological reactions for treatment of metastatic tumors. Furthermore, nanotubes in the proposed photoimmunotherapy could also be used as carriers of other therapeutic drugs as well as imaging contrast agents. Therefore, photoimmunotherapy, combining nanotechnology could potentially become a multi-modality, imaging guided regimen for cancer treatment. We propose to achieve the following specific aims during this one-year collaborative project: 1. To determine the selective thermal effects of the laser-GC-SWNTcombination, using MRT; 2. To determine the in vivo effects of laser-GC-SWNT in the treatment ofmetastatic tumors, using animal models; 3. To determine the immunological effects induced by the laser-GC-SWNT treatment, using immunological assays. The successful completion of this project will pave the way for further research to develop photoimmunotherapy

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The long-term objective of this proposed project is to determine functions of TGF-beta in cancer survellience and intervention and to improve the effectiveness of a novel laser immunotherapy by reducing TGF-beta levels in teh tumor cells. Laser immunotherapy was developed by the PIs, using a near-infrared laser, indocyanine green (ICG, a light-absorbing dye), and blycated chitosan (GC, a proprietary immunoadjuvant) for treatment of metastatic tumors. Our previous studies using laser immunotherapy have shown extremely promising outcomes in the treatment of late-stage, metastatic tumors, both in animal models and in human trials for melanoma and breast tumors. TGF-beta has been shown to be a crucial cytokine in cancer surveillance and intervention. It is hypothesized that reducing TGF-beta levels in tumor microenvironment could significantly enhance the outcomes of laser immunotherapy in treating metastatic tumors through the enhanced anti-tumor immune responses. In this study, we plan to achieve the following specific aims: (1) to reduce TGF-beta levels in DMBA-4 tumor cells for in vitro ain in vivo studies;(2) to determine the effects of TGF-beta reduction on laser immunotherapy treatment of metastatic tumors in rats;(3) to investigate the effects of TGF-beta reducatino on immune cells in the tumor microenvironment. This one-year collaborative grant will allow an initial investigation of the functions of TGF-beta and the mechanism of laser immunotherapy, paving he way for a large-scale, in-depth future study for TGF-beta associated tumor treatment modalities.

DESCRIPTION (provided by applicant): Lasers and nanomaterials are two of the most significant technological advances of the 20th century. The combination of lasers and nanotechnology holds great promise in the fields of biology and medicine. The long- term objective of this project is to develop a multifunctional bionanoprobe for targeted drug delivery, tumor imaging, and photoimmunotherapy for metastatic cancers. The PIs plan to use a novel method (patent pending) to construct a stable solution of single-walled carbon nanotube (SWNT) using a highly potent immunostimulant, glycated chitosan (GC), as an effective surfactant. In this project, the PIs plan to construct, simulate, and calibrate this bionanoprobe, determine its physical and biological characteristics, study its interactions with normal and tumor cells, investigate its toxicity, and determine its photoimmunological effects for treatment of metastatic tumors both in vitro and in vivo. We assume that this bionanoprobe can carry different molecules into tumor cells. We further hypothesize that this novel bionanoprobe, when localized inside tumor cells and combined with laser irradiation of appropriate wavelengths, can induce temporally and spatially synchronized photothermal and immunological reactions for treatment of metastatic cancers. The novelty of this bionanoprobe lies in the unique molecular structures of SWNT and GC so that a strong non- covalent bond can be formed for a stable nanotube solution. Furthermore, selective photothermal interaction can be achieved using in situ SWNT-GC with an absorption peak in the near-infrared region. This ensures a synchronized spatial and temporal thermo-biological effect in target tissue during non-invasive laser irradiation. In this project, the PIs will modify the bionanoprobe with fluorescent molecules to study its cellular distribution and to explore its capability to carry different peptides and therapeutic agents into tumor cells. The PIs will also use magnetic resonance thermometry to determine real-time, 3-dimensional temperature distributions in target tumor tissue during laser irradiation, which could help establish a correlation between temperature increases in tumor tissue and induced immunological responses. Specifically, the PIs plan to achieve the following aims: (1) To construct, calibrate, simulate, investigate, and modify the multifunctional bionanoprobe; (2) To investigate the cellular effects of the multifunctional bionanoprobe; and (3) To determine in vivo efficacy of laser-SWNT-GC for treatment of metastatic cancers. Successful completion of this project will pave the way to future explore the potential applications of this novel multifunctional bionanoprobe in biology and medicine, particularly in cancer treatment.

Project Summary Metastasis causes treatment failure and 90% of cancer-related deaths. We have developed laser immunotherapy (LIT) for the treatment of metastatic cancers. LIT combines local laser photothermal therapy (PTT) and immunotherapy using glycated chitosan (GC), a novel immunoadjuvant, to induce systemic antitumor immune responses. LIT has shown success in clinical trials for late-stage, metastatic cancer patients who had failed conventional treatment modalities. Specifically, LIT has demonstrated its ability to eliminate treated primary tumors and eradicate untreated metastases at distant sites. However, the mechanism of LIT, particularly how it controls tumor metastases, has not been fully investigated. Based on our previous studies, we believe that PTT and GC each induces unique immunological reactions, which, when synergized, produce a systemic, long-term antitumor immunity. Specifically, we hypothesize that: 1) PTT induces immunogenic tumor cell death (ICD), providing antigen sources and damage-associated molecular patterns (DAMPs) to trigger host antitumor immune responses; 2) GC enhances uptake and presentation of antigens generated by PTT-induced ICD, amplifying antitumor T cell response; and 3) LIT synergizes and amplifies the immune responses induced by PTT and GC, particularly when combined with other immunotherapies, such as checkpoint inhibition, providing potent, systemic therapeutic effects, especially on tumor metastases. To test these hypotheses, we plan to achieve the following aims: (1) to determine the photothermal-immunological effects of PTT by determining temperature distribution in tumor tissue and by characterizing the ICD and DAMPs generated by PTT; (2) to determine the effects of GC on immune system during LIT, particularly on activation of T cell as well as enhancement of antigen uptake and presentation; and (3) to determine the effects of LIT, as well as the combination of LIT and checkpoint inhibition, on the enhancement of tumor immunogenicity and on controlling tumor metastasis. The successful completion of this project will achieve the following goals: (1) to obtain a comprehensive understanding of the immunological mechanism of LIT in eliminating and inhibiting metastases; (2) to lay the foundation necessary to advance LIT into an effective treatment modality for patients with a variety of metastatic cancers; (3) to facilitate the development of new, novel treatment strategies using synergistic immunological mechanisms similar to that of LIT, in combination with other complementary therapies, for patients with metastatic cancers.