William Hall - US grants

Many types of experiments indicate that the superior colliculus plays a key role in initiating orienting movements of the head, eyes and ears toward objects of interest. At least three classes of models of the relationship between its structure and function can be distinguished: those proposing that pathways between the layers of the superior colliculus integrate the sensory and motor systems involved in initiating orienting movements; those arguing that the layers are independent and serve mainly to distribute information to different destinations; and those proposing that connections between compartments within individual layers provide the substrate for interactions between the sensory and motor systems. The specific aims of this application are to test these models. Because of technical limitations, past anatomical studies have provided few clues to intracollicular circuitry. Consequently, current models have been based primarily on physiological properties of collicular neurons, such as the latencies of their responses and properties of their connections, but the postulates are difficult to test with physiological methods. The proposed research will test the current models directly by intracellularly injecting cells of each layer and tracing their intracollicular connections, using living brain slices from the tree shrew, Tupaia belangeri. Relative to other commonly studied species, this primate-like mammal has an especially large and well differentiated superior colliculus, which greatly facilitates the task of analyzing the connections between the layers. In some cases, cells will be prelabeled by retrograde axonal transport so that the injected cells can be identified by the extracollicular destinations of their axons, in addition to their location, morphology and intracollicular connections. In other experiments, sensory or motor pathways to the superior colliculus will be prelabeled to determine whether they converge on collicular neurons of different types. These experiments are designed to provide a framework for new models based on knowledge of intracollicular circuitry and, in this way, will contribute to our understanding of the neural mechanisms underlying sensorimotor integration in the vertebrate brain. receptive and movement fields.

Studies aimed at establishing new building design approaches which incorporate innovative concepts relating to force, deformation, energy, and economy will be conducted. This work will address important problems in the relationship between ground motion and system resistance in terms of the system's cyclic behavior and energy absorption, system modeling for both linear and nonlinear responses, and upgrading of design approaches.

The marine sciences are of interest to students K thought undergraduate school. However computer-aided instruction in the marine science appears to be limited to approximately twenty-four software programs currently available for microcomputers. This project is directed at the 6-12 grade levels in the area of marine biology The objectives are: to design a lesson to demonstrate the form and function of fishes; to involve students actively in the learning process by providing a computer environment for manipulating fish form, function and habitat in order to "design a fish"; and to demonstrate the concept that evolution is a function of environmental dictates. The Apple IIc or IIe computer will be used in the development because the Apple II Series is currently the microcomputer used most extensively in the precollege level schools. Evaluation of the lesson will proceed through the Delaware Department of Public Instruction, using Delaware schools. In addition to various inservice programs, the Mid- Atlantic Marine Education Association and the National Sea Grant Program will be evaluating the materials. Marketing will be done through the University office of Instructional Technology. This project makes excellent use of the appropriate technology in a most suitable fashion. Secondly, the product has high potential to serve as a model for future development in other disciplines. The availability of good software in the area of biology is very low so a real need is being met by highly qualified persons and with a modest budget.

Recent earthquake observations (e.g., 1985 Mexican Earthquake) confirm that failures of buildings often involve the torsional mode of response. Study of the data from the extensively instrumented buildings that appear quite symmetric. This project, through the use of simple models, will investigate the observed response of two low- rise buildings, in both the elastic and inelastic domains. The studies also will investigate the response of these same buildings if subjected to a stronger earthquake. Observations pertaining to provisions for future building codes will be provided. The aim is to develop a better comprehension of torsional effects arising from seismic base motion. This research would clarify the not yet well understood phenomena of torsional effects in the dynamic response of low-rise buildings.

9353232 Hall This planning grant will aid Delaware in writing a teacher enhancement proposal to address their middle school science needs. A process has been described that includes Delaware's SSI project; outside consultants, and Middle school teachers in defining the needs and direction for middle school science. Specifically, meetings will be held, survey tools will be developed to evaluate the current status of science in middle schools, and teachers will hold community meetings to explain the need for science education reform and obtain input on the proposed direction for middle school science. The planning grant will involve at least 30 middle school science teachers. The project duration is 12 months beginning June 1993 and ending June 1994. There is no cost share for this project.

Studies from our laboratory have focussed on the molecular and immunological properties of human T-cell lymphotropic virus type II. Employing virus isolates from our patient population we have demonstrated that there are in fact three molecular subtypes of the virus which have now been designated HTLV-IIa, IIb and IIc. Preliminary studies have also suggested that these may be phenotypic differences between the three subtypes. Specifically it could be shown that the tax protein which is believed to be important in HTLV leukemogensis differs between the subtypes and current studies are underway to determine if this may result in idfferences in subtype pathogenicity. In our immunological studies we have focussed on the tropism of HTLV-II infection in vivo and investigated whether infection porduces clonal expansion of the infected cell populations. These studies have shown that all three virus subtypes have a preferential tropism for CD8+ T lymphocytes. In addition the infection does appear to cause expansion of these. Studies underway and in the future will determine the role of virus regulatory proteins in this process, and the importance of expansion as an early event in virus- induced leukemogenesis.

Acute viral respiratory tract infection (ARTI), especially that caused by infection with respiratory syncytial virus (RSV) and influenza, causes excess rates of hospitalization and increased mortality in older persons. In addition, ARTI is a common cause of involuntary immobility in frail elderly, often setting into motion a cascade of events resulting in substantial disability, functional decline, and subsequent loss of independence. The Rochester AREA Pepper Center (RAPC) has begun to define the epidemiology, clinical characteristics, and impact on functional state of these common illnesses, focusing on the frail elderly in the setting of adult day centers and in long term care facilities as the most vulnerable populations of older persons. A postulated linkage between acute infection and cardiovascular events is supported by a growing body of literature. The common linkage between these two important phenomena may be alterations in the hemostatic system related to inflammatory and immunologic responses to viral infection. A better understanding of the immune response to infection in older persons, and its relationship with the hemostatic system may lead to a number of specific interventions including targeted immunization, anticoagulation strategies, or remediation of defects in the immune system by improved nutrition. The Intervention Development studies proposed have the following aims: 1. Define the heterogenicity of the immune response as a function of age and define potentially reversible aspects. 2. Determine whether immune biomarkers may be predictors of more severe ARTI. 3. Evaluate the host response of older persons to natural infection with influenza an RSF. 4. Identify hemostatic parameters associated with risk of vascular events in the same cohort of frail elderly. 5. Investigate the reaction between acute viral infection and a prothrombotic state. 6. Trial immunomodulatory interventions. 7. Evaluate the role of low intensity anticoagulation. Controlled clinical trials have been designed. Testing will include viral diagnostic methods, measures of cellular and humoral immunity, hemostatic determinations, and geriatric functional assessment.

technology /technique development; virus; proteins; enzymes; biomedical resource;

We have had our newly developed mass spectrometric protein identification and protein elucidation tools to characterize the mature protein components of human T-cell leukemia virus types I and 11. A paper describing this work has been published (Qin, et al. Anal Chem. 69, 3995-4001, 1997).

The renewal of the Rochester Area Pepper Center (RAPC) builds on the experience of the previous 3 + years. The current RAPC's 2 intervention (IS) and 2 intervention development (IDS) studies focused on evaluating ways to improve or maintain the functional status of the elderly at various stages of physical dependency using standard exercise or pharmacologic interventions and pre- and post-treatment methods of functional assessment. Excellent progress has resulted in 23 publications from the IDs or IDSs, 93 from research of RAPC faculty, and 49 from work funded by the RDC. Despite past progress, the new proposal moves in a new direction. We will integrate basic mechanistic research into 3 clinical IDSs. IDS#1 extends our successful IS of Acute Respiratory Tract Infections (ARTI) in the frail elderly to determine if alterations in immunologic and thrombotic status are predisposers or contributors to, the functional decline noted in ARTI. IDS#2 builds on the current IS findings showing that resistance exercise training does not greatly improve myofibrillar protein synthesis in healthy elderly subjects. The new goal is to determine if a 'more youthful' rate of myofibrillar protein synthesis will result from gonadal steroid therapy thus minimizing the age-related skeletal muscle atrophy. In IDS#3 complementary approaches will be used to study the disease- or age-related declines in neural mechanisms governing spatial orientation and equilibrium control. These approaches include standing balance (postural control), eye-head and eye- head-hand coordination, and visual motion processing that distinguishes self- from externally -initiated movements. The goal is to clarify the parameters that maintain and influence sensory-motor integration between subject and environment. Research Development (RD), Research Resource ; [Biostatistics (RRB)], Demonstration and Information Dissemination (DID), and Administrative (LA) Cores contribute to all RAPC functions. The Cores a) provide seed money for new initiatives and to support the career development of junior faculty (RD); b) provide methods (RRA) for accurate assay of glutathione metabolism for the IDS and other ongoing research; c) assist in the experimental design and statistical analysis of data (RRB); d) inform the medical and lay communities of the RAPC's work and publicize its educational programs (DIDC); and e) provide the leadership, administrative structure and oversight (LA) needed to fulfill the goals of the IDS and Cores. The abiding principle in developing the new RAPC was that its studies and functions, relate and contribute to ongoing clinical and research programs at the U of R Medical Center thereby enhancing the Center's function and significance.

[unreadable] DESCRIPTION (provided by applicant): GABAergic inhibitory circuitry within the intermediate layer of the superior colliculus plays an essential role in generating the premotor signals that initiate shifts in the direction of gaze. However, the spatiotemporal dynamics of this inhibition remain unclear. We will use Clomeleon, a genetically-encoded Cl- indicator, to image in real time the spatial organization of Cl- dependent synaptic inhibition. We have produced transgenic mice that express Clomeleon in premotor cells of the intermediate layer. Clomeleon chronically expressed in these neurons is capable of responding to Cl- fluxes associated with activation of GABAA receptors. We propose to use these Clomeleon mice to determine whether Clomeleon is sufficiently sensitive to detect the changes in [Cl-]i that are generated in the premotor cells by stimulation of GABAergic pathways. To test the hypothesis that activation of premotor cells in a region that commands gaze shifts in one direction inhibits the [unreadable] activity of cells in other regions that would command competing gaze shifts toward stimuli in other directions, we will use Clomeleon to visualize the spatiotemporal distribution of inhibition throughout the intermediate layer that is evoked by activity within one region of this layer's spatial map of gaze vectors. This approach of functional imaging CI-mediated inhibition potentially can be applied to the study of inhibitory circuitry in any brain area. [unreadable] [unreadable] [unreadable]

[unreadable] DESCRIPTION (provided by applicant): This Training Program in Geriatrics and Gerontology seeks to produce independent academic investigators in clinical and health services research, whose focus is improving function in older adults. The program will accept 2 postdoctoral fellows per year, so that at a steady state, 4 fellows would be participating. They will be recruited primarily from the geriatrics fellowship based at Monroe Community Hospital, but will also be accepted from the Departments of Community and Preventive Medicine and of Psychiatry, as well as the School of Nursing's Center for Clinical Research on Aging. They will participate in a 3-part training program over a two-year period. The 3 components are: 1) a mentored research experience; 2) a series of 7 didactic courses aimed at acquiring the knowledge necessary for conducting clinical research, including biostatistics, epidemiology, and design of clinical trials; and 3) a series of workshops to build research skills, including research ethics, scientific communication, medical informatics, and grant writing. The latter two components of this training plan will utilize the Rochester Clinical Research Curriculum, a highly successful program developed through an NIH K30 award to train clinical researchers. Mentors will be chosen from 5 research "clusters": cardiology, geriatric health services, neuropsychiatry, oncology, and infectious diseases. In addition to a Primary Research Mentor, fellows will work with one or more Geriatrics / Gerontology Faculty Advisors, so that they will have a mentorial panel that can provide an optimal training experience. [unreadable] [unreadable]