Christopher Rhodes - US grants

DESCRIPTION (provided by applicant): It has now been realized that type-2 diabetes is a disease of insulin insufficiency. Type-2 diabetes is associated with a decrease in functional pancreatic [unreadable]-cell mass that no longer compensates for the peripheral insulin resistance. As such, maintaining an optimal [unreadable]-cell population for the insulin secretory demand, especially by promoting [unreadable]-cell survival, is key for delaying the onset of type-2, as well as type-1, diabetes. In this regard, IRS-2 has been shown to play a pivotal role in [unreadable]-cell growth and survival. Increased IRS-2 expression promotes [unreadable]-cell growth and survival, whereas insufficient IRS-2 expression leads to spontaneous [unreadable]-cell apoptosis. Although IRS-2 protein and mRNA half-life is short in islet [unreadable]-cells, this is countered by efficient and highly regulated control of IRS-2 expression, predominately mediated at the transcriptional level. Under basal conditions, [unreadable]-cell IRS-2 gene transcription is controlled by a FoxO transcription factor via an insulin response element (IRE) in the IRS-2 promoter. When IRS-2/PI3K/PKB signaling is activated in [unreadable]-cells, FoxO transcription factors are consequently inactivated and IRS-2 expression is reduced, in what appears to be a temporal negative feedback mechanism to prevent IRS-2 signaling from being sustained. However, IRS-2 expression can be independently controlled in [unreadable]-cells by alternative means. Glucose, in the physiologically relevant range, is a major regulator of [unreadable]-cell IRS-2 gene transcription. This requires glucose metabolism and is Ca2+-dependent. It likely provides a mechanism to preserve [unreadable]-cell well-being during acute changes in metabolic demand, and is important since other factors, like incretins, only increase IRS-2 expression in [unreadable]-cells in a glucose-dependent fashion. However, these early findings need substantiating. This proposal means to gain a better insight into the control of IRS-2 expression in pancreatic [unreadable]-cells at the molecular level. It is intended to better characterize control of IRS-2 gene transcription under basal conditions with an emphasis on identifying which particular FoxO transcription factor downstream of PI3K/PKB signaling increases IRS-2 expression. In addition, we will pinpoint which particular secondary signals emanating from increased glucose metabolism in [unreadable]-cells link to increased IRS-2 expression (especially via Ca2+/CaMK). It is intended to define a glucose-regulatory cis-element(s) (GREs) in the IRS-2 gene promoter and then identify a trans-acting factor(s) that specifically associates with the GRE glucose-regulatory manner. Thus, a much deeper insight into the molecular mechanism that controls IRS-2 expression in normal, obese and type-2 diabetic primary [unreadable]-cells will emerge from these proposed studies. Obesity-linked type-2 diabetes is a major health problem in the US and caused by loss of pancreatic [unreadable]-cells that produce insulin. Novel therapeutic approaches are needed which are aimed at protecting the endogenous [unreadable]-cell population to produce enough insulin to delay, perhaps indefinitely, the onset of diabetes. IRS-2 is a gene key to [unreadable]-cell survival, and it is anticipated that new insight into the control of IRS-2 expression will lead to a novel means of maintaining adequate [unreadable]-cell numbers and sufficient insulin production in vivo, that in turn will alleviate, or perhaps even prevent, symptoms of type-2 diabetes. PUBLIC HEALTH RELEVANCE: Type-2 diabetes is caused by a decrease in functional pancreatic [unreadable]-cell mass that is no longer able to compensate for the peripheral insulin resistance, and thus maintaining an effective [unreadable]-cell population by promoting [unreadable]-cell survival and protection is key for delaying the onset of type-2 diabetes. IRS-2 plays a pivotal role in [unreadable]-cell growth and survival, and its expression is tightly controlled (predominately at the transcriptional level), but little is known about this regulation. The overall goal of this application is to get better insight into the molecular mechanism behind transcriptional control of IRS-2 in [unreadable]-cells, that may eventually lead to a novel therapeutic means of promoting [unreadable]-cell survival via maintaining optimal IRS-2 expression to subsequently delay, perhaps indefinitely, the onset of diabetes.

DESCRIPTION (provided by applicant): Metabolic disease is a massive worldwide health problem as illustrated by the current epidemics in obesity and type 2 diabetes, which is especially prominent in the United States and showing no sign of abating. As such, there is an urgent need for metabolism research to face this alarming situation. However, there are relatively few training programs across the country specifically dedicated to the training of bright young researchers in metabolism at the systemic, cellular and molecular level. To address this need we have set up the Molecular Metabolism Training Program (MMTP) at the University of Chicago which incorporates the Committee on Molecular Metabolism &Nutrition (CMMN) that is one of the few, perhaps the only, graduate programs in the United States granting a PhD in molecular metabolism. A successful training program in metabolism requires a multi- and inter-disciplinary approach, made up of researchers with a wide variety of technical skills and research experience. The MMTP takes advantage of the marvelous and highly interactive biomedical environment and strong traditions in metabolic and diabetes research at the University of Chicago. The trainers in the MMTP, in whose laboratories MMTP trainees will conduct their research projects, have primary appointments across many departments and sections of the Biological Sciences Division, to cover most of the diversity in metabolism research. Being interdepartmental, the MMTP pre- and postdoctoral trainees can take courses and gain experience in Biochemistry, Molecular Biology, Cell Biology, Genetics, Medicine, Pathology, Immunology, Physiology and Neurobiology with a required comprehensive specialized metabolism core-curriculum. Trainees are also required to attend metabolism journal clubs, data sessions, seminar series, and an annual retreat. Participation in National and International metabolism, diabetes and/or obesity scientific meetings is expected. There is strong institutional support, as well as a significant allocation of new research space and equipment for this fast growing MMTP. Many outstanding applicants apply to the MMTP and the recruitment success rate is very high. Pre-doctoral trainees recently graduated from the CMMN/MMTP have found postdoctoral positions in outstanding academic metabolism research laboratories. Although newly established, the ultimate goal of the MMTP is to set up young researchers on the path to become independent academic metabolism research scientists and mentors themselves - dedicated to excellent scholarship and making breakthrough discoveries in metabolic disease and diabetes/obesity research that will lead to new therapies to better treat, prevent and perhaps even cure these disorders. PUBLIC HEALTH RELEVANCE: Metabolism is required for life and impinges on almost every disease state, but despite this fact, as well as a resurgent interest for metabolic disease research (partly driven by worrisome epidemics in obesity and diabetes), there are insufficient specialized basic/translational researchers to tackle these huge metabolic health problems. The newly established MMTP at the University of Chicago has clear relevance to produce much needed, highly qualified and experienced young researchers specialized in molecular metabolism to make new discoveries that in turn benefit the many who suffer from metabolic diseases like diabetes/obesity.

NON-TECHNICAL DESCRIPTION: The low energy stored within current day batteries limits the size and weight of contemporary electronics ranging from consumer electronics to medical devices. A new generation of high energy density power packs is needed. In this project, the unprecedented ability of vanadium diboride to release an exceptional 11 electron per molecule yields an energy density substantially greater than that of lithium or zinc, and provides the opportunity to greatly enhance the energy density of power packs. Today's batteries and fuel cells deliver only one or two electrons per molecule. Remarkably, the 11e- storage capacity of vandium diboride is released over a flat, favorable, singular discharge voltage. Little is known regarding the limiting mechanisms of this unusual process. The unique electrochemical properties of VB2 will be explored in this project. This GOALI project is a collaborative university-industry effort to understand the unusual and promising redox storage process of new energy dense, multi-electron materials for batteries and fuel cells.

TECHNICAL DETAILS: In this project, the unprecedented ability of vanadium diboride to release an exceptional 11 electron per molecule will be explored to greatly enhance the energy density of power packs. This VB2 charge density is substantially greater than that of conventional battery anodes based on lithium or zinc. Remarkably, the 11e- storage capacity of vandium diboride is released over a flat, favorable, singular discharge potential plateau. Little is known regarding limiting mechanisms of this unusual process, and the unique electrochemical properties of VB2 nanoparticles will be explored in this project. This research, provides the first foray into the nano-domain of VB2 (anodic) electrochemistry. Stabilizing zirconia coated nanoparticle architectures will be studied to facilitate this unusual 11 electron anodic process and to formulate in a library of new VB2 nano-composites. A fundamental understanding of these processes will be developed towards the transformative goal of a new generation of power packs with several fold higher capacity than existing batteries and fuel cells. Cell configurations will be optimized to maximize the capacity of a VB2/air energy storage cell. This GOALI project is a collaborative university-industry effort to understand the unusual and promising redox storage process of new energy dense, multi-electron materials for batteries and fuel cells. The George Washington University (GWU) postdoctoral scholar and graduate and undergraduate researchers participating in this project will be trained in state-of-the-art fundamental electrochemistry at GWU and have the special opportunity to gain experience in the industrial R&D workplace through visits each year to the industry liason, Lynntech, Inc.

? DESCRIPTION (provided by applicant): Obesity-linked type 2 diabetes is a major health problem of worldwide epidemic proportions. The onset of the disease is marked by failure of the functional pancreatic islet ß-cell mass to meet metabolic demand, and is thus an insulin insufficient state. It follows that a means to protect and preserve adequate functional ß-cell mass has therapeutic potential for type 2 diabetes. Much is known about nutrient and hormonal regulation of ß-cell function. However, despite it being known for more than 160 years that the central nervous system (CNS) has a significant degree of control over pancreatic islet functions, mechanisms of CNS control over pancreatic ß-cells remain vague. Indeed, the precise regions of the CNS that link to pancreatic islets are unknown. In this proposal it is intended to utilize a novel class of pseudorabies viral vectors (PRV) as retrograde transynaptic neuronal tracers to accurately track the neuronal link between pancreatic islets and specific regions of the CNS in vivo. This will be complemented by several in vivo anterograde-tracing techniques to refine the PRV retrograde tracing. Aim-1 will use both retrograde and anterograde neuronal tracking approaches to reveal a CNS `brain-to-islet topographical map' in mice, at a 5µm-resolution and in 3D. This map will be characterized in detail, particularly to unveil what kind of neuronal cells are within it and to utilize novel anterograde-tracking techniques to identify specific neuronal circuitries that can be activated within this map. In Aim-2 glucose-sensing neurons within the `brain-to-islet map' will be manipulated, using accurate stereotaxic delivery of adenoviral vectors that alter glucokinase activity in specific sub-regions of the hypothalamus. Likewise, in Aim-3, a similar stereotaxic approach will be taken, but aimed at specifically targeting particular hypothalamic insulin-signaling neurons, where insulin receptor and IRS-2 gene function will be manipulated. Then, it will be assessed whether alteration of glucose-sensing and/or insulin-signaling in regions of the CNS which link to pancreatic islets will affect islet cell function in ivo, particularly in regard to control of ß-cell mass, insulin and glucagon secretion. This will be measured relative to metabolic homeostasis and insulin sensitivity, so as to distinguish between direct acute effects of the CNS on islet cell function rather than peripheral metabolic effects to which islet cells act secondarily. Thus, the newly revealed `brain-to-islet map' will be validated as a functional guide, and novel mechanistic insight into CNS neuronal control of pancreatic islet cell functions gained. It is anticipated that this research will eventually translate into noel therapeutic approaches for the treatment of diabetes/obesity.

Non-technical:
This Major Research Instrumentation (MRI) grant awarded to Texas State University at San Marcos (TxState) provides funding for the acquisition of an Atomic Force Microscope (AFM). This high-resolution instrument enhances the research and educational capabilities at TxState, a Hispanic Serving Institution. Because AFM data is highly visual, the results are accessible to non-scientists and will thus engage students not already committed to STEM. The proposed instrument acquisition will immediately impact 58 students and postdocs upon acquisition (with hundreds of additional users over the lifespan of the instrument). The addition of this tool to TxState, where 55% of the students and postdocs are underrepresented in science and engineering, will have a long-term impact on a diverse population of students and the institution in which they are trained. In addition, this acquisition strengthens, in particular, the research activities of the NSF-funded PREM Center on Interfaces in Materials (PREM: Partnerships in Research and Education in Materials). A primary goal of the PREM Center is to increase the participation of underrepresented minorities in materials research. Data from this instrument will impact energy and medical-related research projects that are intended to enrich our lives.

Technical:
Atomic Force Microscope (AFM) is a scanning probe technology that identifies surface features at the nanometer scale. AFM will be used by Texas State University at San Marcos (TxState) to advance fundamental surface science and applications in energy and biomaterials-related research topics. Specifically, this acquisition of a AFM Workshop Life Sciences AFM will impact the following materials research areas: 1) nanocomposites, 2) self-assembly of photoactive bioconjugates, 3) nanomaterials for energy storage and conversion, 4) metallo-supramolecular assembly, 5) perovskite solar cells, and 6) stimuli-responsive biomaterials.

This Major Research Instrumentation grant provides funding for the acquisition of a vibrating sample magnetometer (VSM) used for the characterization of magnetic materials. A VSM is used to determine the magnetic hysteresis curve, i.e. the relation between the magnetic field and the magnetic moment. The hysteresis curve provides the magnetic response of the material under an applied field and is often referred to as the magnetic fingerprint. The VSM allows the measurements of the magnetic moment both parallel and perpendicular to the applied magnetic field. This unique instrumental feature is crucial to the understanding of magnetic properties as magnetic moment and field are vector quantities that have in addition to a magnitude also a direction. The instrument is used to study thin film and powder materials that are currently being investigated at Texas State University. The VSM acquisition enhances the research in at least 8 different academic groups across 5 different programs. Research projects impacted by the new VSM include studies of (1) new permanent magnetic materials to be applied in wind turbines and generators, (2) two-dimensional (2D) materials for electrochemical energy storage, (3) nanocomposite materials with superior mechanical properties, and (4) novel metal oxide thin films for applications in sensors, actuators, and new non-volatile memory devices. The VSM instrument will enhance education and research within Texas State which is a Minority-serving Institution with a significant population of 1st generation students and students from underrepresented groups. The VSM further enable development of a meaningful collaboration with a regional start-up company, Urban Mining

Texas State University proposes to acquire a high field vector vibrating sample magnetometer (VSM) for the characterization of magnetic materials including powders, thin films and bulk magnetic materials. This vector VSM allows the study of the magnetization and magnetic anisotropy over a wide temperature, field magnitude, and field direction range. The fast temperature and field control and the simplicity and robustness of tool enables the use of the new VSM as a work-horse magnetic characterization tool and effectively implement it in Texas State University undergraduate and graduate curriculum. The VSM acquisition enhances the research in at least 8 different academic groups across 5 different programs. Proposed research includes studies of the magnetic properties of: defect clusters in RRAM transition metal oxides, low dimensional systems, specifically hydroxides and oxyhydroxides that are being studied for applications in batteries, hard magnetic materials including NdFeB permanent magnets, novel spintronic devices and the role of oxygen vacancies, thin ferromagnetic films grown by MBE, RF sputtered BFO films for application in novel sensors and applications, and printed magnetic thin films for use in meta-materials.