Wise Young - US grants

In the past 5 years, significant advances have been made in our understanding of pharmacological therapy of acute spinal cord injury, to the extent the several controlled multicenter clinical trials are underway. A three day conference devoted to a detailed and critical review of the pharmacological treatments of acute spinal cord injury is proposed. Two classes of drugs will be specifically targeted for review: steroids and opiate receptor blockers. Funds are requested to cover the per diem and travel expenses of 10 invited speakers to this conference. The conference will be in 3 parts. The first is concerned with the theoretical basis and mechanisms of these two classes of drugs. The second will focus on the laboratory studies indicating efficacy. The third will cover the current clinical trails. The proceedings of the conference will be published within 6 months after the conference and distributed widely to researchers and clinicians interested in pharmacological treatments of spinal cord injury. Specific aims of the conference include not only better dissemination of information concerning treatments of acute spinal cord injury but clarification of the mechanisms of high dose steroids and opiate receptor blockers as treatments of central nervous system injury. It is hoped that by bringing together researchers investigating these two classes of drugs, the discussion will yield insights into commonalities between the two. The conference will be held at NYU, under the auspices of the NYU Post-graduate School of Medicine, in Spring of 1987. The proceedings will be published as a supplement to the journal CNS Trauma.

Large tissue net ionic shifts are associated with cerebral edema after middle cerebral artery occlusion (MCAo). The net ionic shifts correlate highly with water concentration changes with regression slopes of 150-160 mu moles/ml, close to plasma ionic concentrations, suggesting that ionic shifts caused edema since participation of other osmotic agents would reduce the slope. The causes of the net ionic shift are not known. We will test the hypotheses that (a) net ionic shifts result from differences in extracellular Na and K gradients driving Na entry and K loss and (b) glial K uptake causes different in the Na and K gradients. Extracellular Na and K will be measured with ion-selective microelectrodes after MCAo and compared with tissue ionic and water shifts. Albumen and IgG passage across the blood brain barrier, regional blood flow, blood pressure, and plasma ionic levels will be monitored. Ionic shifts will be investigated in rat cortical freeze lesions. Freezing disrupts glial cells, prevent K uptake, and thereby should reduce net ionic shift and edema. The effects of systemic furosemide, mannitol, and/or methylprednisolone on extracellular and tissue ionic shifts will be studied in the rat MCAo and cortical freeze models. Neurophysiological and morphological changes will be correlated with ionic shifts. These studies will clarify ionic mechanisms in edema, relate tissue ionic shifts to tissue damage, and establish rational bases for treating ionic edema in stroke.

This is an established clinical spinal cord injury research center. Four research projects and a core facility are proposed. Project 1 (Experimental Therapy) will examine the time course and relationships of tissue ionic and phosphate shifts to traumatic injury. Three hypotheses will be tested: that phosphates released by lipid peroxidation bind Ca ions and cause the depression of extracellular Ca activity observed in injured spinal cords, that the fall in extracellular Ca activity protects neurons, and that return of extracellular Ca causes secondary tissue damage due to excessive Na/Ca exchange. Treatments stemming from the hypotheses will be assessed. Project 2 (Extracellular Ionic and pH Regulation) will investigate the mechanisms of extracellular ionic changes in acute and chronic injured spinal cords. Ion-selective microelectrodes will be used to determine the extent to which extracellular Na, K, Ca, and Cl ionic changes are due to equilibration and are prolonged due to extracellular space constriction, and to ascertain whether acid production and tissue injury are governed by ischemia and serum glucose levels. Project 3 (Axonal Dysfunction) will study axon conduction in dorsal columns of injured spinal cords, utilizing a new random double pulse stimulation method to characterize supernormal behavior, fatigue, and refractory period in injured and demyelinated axons after spinal cord contusion and compression. The experiments will test the hypotheses that injured axons release more K ions and are more sensitive to extracellular K ionic activity changes. Project 4 (Recovery of Motor Dysfunction) will characterize changes in lumbosacral segmental excitability and interactions of residual descending tract activity with these segmental changes after spinal cord injury, focussing on the the effects of 4-aminopyridine, a blocker of voltage-sensitive K channels, on axonal conduction and segmental excitability. The Core Facilities will support the research effort in the center by providing basic histological and physiological services, and animal care support. Positions for a clinical and a laboratory spinal cord injury fellow are requested the aim of training independent investigators in clinical and basic research on spinal cord injury. The overall goals of this Center are to elucidate mechanisms of axonal loss and dysfunction in spinal cord injury and to establish a rational basis for treatments of spinal cord injury.

The overarching objective of the work proposed here is to support a productive interdisciplinary collaboration that will simultaneously generate meaningful quantitative research results in the neurosciences and foster the acquisition of the physiological background that will permit me to develop an independent research program in quantitative modeling of neuronal morphogenesis. The proposed work will be performed at the Center for Collaborative Neuroscience at Rutgers University, and will focus on developmental and regenerative mechanisms associated with Dorsal Root Ganglion (DRG) neurons and their associated glia. This work will involve two research projects to be performed under the guidance of Prof. Wise Young, MD PhD and Chair of Cell Biology & Neuroscience, and Prof. Martin Grumet, PhD and Director of the Center, in close collaboration with appropriate faculty, postdoctoral fellows, graduate students, and visiting scientists affiliated with the Center. The aims of this work are to quantitative test the hypotheses that morphogenesis of Dorsal Root Ganglion (DRG) neurites in vitro can be well described by a stochastic model, and that the function of such stochastic morphogenesis is to efficiently explore space in search of targets. The approach that will be used to achieve these aims will involve direct numerical simulations of axonal and glial structures that are validated and modified to accord with 3D imaging of neuronal cultures. Throughout this work, the guiding objective will be to use modeling to derive concrete, testable predictions.

This IGMS project is jointly supported by the MPS Office of Multidisciplinary Activities (OMA) and the Division of Mathematical Sciences (DMS).