Todd T. Gleeson - US grants

DESCRIPTION (Adapted from the applicant's abstract) Gluconeogenesis is the principal mechanism of maintaining blood glucose levels within narrow limits during periods of fast, starvation, and exercise. Gluconeogenesis can also function to replenish depleted muscle glycogen stores after strenuous exercise. While lactate can serve as substrate for gluconeogenic replenishment of muscle glycogen following activity, most studies of mammals have indicated that the fate of most post-exercise lactate is oxidation to CO2 and H2O. Recent research has demonstrated that the major fraction of post-exercise lactate is gluconeogenically converted back to muscle glycogen in the lizard Dipsosaurus dorsalis. Even more striking was the observation that the site of gluconeogenesis was skeletal muscle rather than the liver, as is the case in mammals. In fact, lactate is the preferred substrate for glycogenesis in lizard muscle. In vivo and in vitro data demonstrate that red muscle has a greater capacity for glyconeogenesis than does white muscle, but that lactate incorporation into glycogen in both muscle types is stimulated by post-exercise levels of epinephrine. The proposed research will continue investigation of this strategy of lactate and glycogen metabolism through a side-by-side comparison of mouse and lizard muscle. The investigators' aim will be to determine the hormonal and biochemical mechanisms in muscle that result in lactate-supported oxidation in one case, and lactate-supported glyconeogenesis in the other. Experiments will investigate the regulation of muscle gluconeogenesis in vivo and in vitro by pH and by hormones, factors which change during recovery from exercise. Preliminary data indicate that activities of enzymes thought to regulate glycolytic/gluconeogenic flux change during the rest-to-recovery transition. The activities of enzymes such as PK and PEPCK, PFK and FDPase, and glycogen synthase and phosphorylase will be examined during this transition, and the effects that select hormones (insulin, epinephrine, corticosterone, and glucagon) have on these changes will be studied to determine possible mechanisms for hormonal regulation. The capacity and regulation of liver lactate metabolism under the same conditions will also be examined, as recent reports question whether or not lower vertebrate liver has any significant role in post-exercise metabolism. Nine experiments are described, the results of which, when taken together, will describe the process and regulation of lactate metabolism following exhaustive exercise in a vertebrate with gluconeogenic skeletal muscle, and contrast that to mouse muscle which lacks this gluconeogenic propensity. These studies are intended to describe in a more integrated fashion the metabolic function of "gluconeogenic" skeletal muscle following vigorous activity, its enzymatic and hormonal regulation, and the reduced role that liver apparently plays in the recovery process.

Most of our insight into the energetics of terrestrial locomotion is derived from studies of metabolic expenditure of animals running under steady-state (constant speed, long duration) conditions. Non-sustainable locomotion of high intensity but short duration, of the type seen during prey capture, territorial defense, or predation avoidance represents behavior at least as important as long duration sustained locomotion, and is a type of activity with different metabolic underpinnings. This research will examine the energetics of this type of activity. The PI will investigate four aspects of non-sustainable locomotion: 1) the effects of duration, 2) the effects of different locomotor intensities, 3) the differential responses of an endotherm vs. an ectotherm to brief exercise, and 4) the role of hormones in defining this locomotor cost. The study addresses a realm of animal activity for which we have no predictive database. The preliminary data suggest that the net cost of non-sustainable locomotion may be an order of magnitude more expensive than when animals cover the same distance at aerobically sustainable speeds. If supported by the proposed research, this finding will raise fundamental questions about the consequences of some types of animal behavior, and open a new chapter in the study of animal locomotion.

The goal of this project is to contribute to the development of a national science and engineering academic workforce that includes the full participation of women in all levels of faculty and academic administration, particularly at the senior academic ranks, through the transformation of institutional practices, policies, climate and culture. Through the Leadership Education for Advancement and Promotion Program (LEAP), the University of Colorado seeks to transform the makeup of the science and engineering faculties at the University of Colorado, Boulder, and to increase the number of women trained in the scientific, mathematical, engineering, and technology (SMET) disciplines serving in key administrative positions. The University of Colorado, Boulder seeks to improve the environment for all faculty members, by improving the level of managerial and leadership skills possessed by the faculty. Providing all the tools needed to work effectively will reduce the stresses commonly associated with achieving tenure. LEAP will therefore accelerate the promotion rate of women faculty by increasing retention rates and making their environment more supportive. The program is designed to keep faculty members on track for tenure, to identify potential leaders, and to give people more leadership opportunities.

The program is designed to work with efforts already underway at the University of
Colorado. Formative evaluation of the program will maximize the effectiveness of the funds used over the lifetime of the program. At the end of the five-year period the University of Colorado, Boulder expects to have more women in leadership positions in the University. In addition, they will have trained a cadre of faculty better able to pursue long term change, and have developed an effective way to continue to train faculty for success. This program will permanently impact the institution and the changes it initiates will be self-sustainable through internal support.

This project is supported by the NSF ADVANCE Program. The overall mission of the ADVANCE Program is to increase the participation of women in the scientific and engineering workforce through the increased representation and advancement of women in academic science and engineering careers.

This project will start a long term collaboration between the mathematics department and the biology department at the University of Colorado-Boulder. There is a tremendous amount of physiological data on the Mouthner nerve cell that has been collected in the past twenty five years. This project will start the development of a sophisticated mathematical and computational model of this cell that will incorporate the known data. New computational methods will be developed for massively parallel computers to model the
dynamics of this nerve cell. It is intended that this project will start a significant program in computational neuroscience that will become an option for the Ph.D. program in neuroscience at the University of Colorado. In addition, the undergraduate research program that this project grew from will continue to engage undergraduates in research in computational neuroscience. This IGMS project is jointly supported by the MPS Office of Multidisciplinary Activities (OMA) and the Division of Mathematical Sciences (DMS).

The University of Colorado is establishing a Distributed Center for STEM Education Research and Transformation that integrates education projects across the campus. The Center addresses the three themes outlined in the National Academy of Science report "Rising Above the Gathering Storm". These are: (1) Teachers in K-12 education (10,000 Teachers, 10 Million Minds), (2) Research (Sowing Seeds), and (3) Higher Education (Best and Brightest). This Distributed Center involves eight traditional departments in three colleges and schools, including: Education, Life Sciences, Mathematics, Physical Sciences, and Engineering. Existing education projects being integrated into the center include: ADVANCE (Increasing the Participation and Advancement of Women in Academic Science and Engineering Careers); Course Curriculum and Laboratory Improvement projects; Robert Noyce Teaching Scholarship project; Integrative Graduate Education and Research Traineeship projects; and Research and Evaluation on Education in Science and Engineering projects.