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Abstract

Grant Number:	1R43NS046157-01
PI Name:	GABBITA, SOMASUNDAR P.
PI Email:	pgabbita@phase2d.com
PI Title:
Project Title:	Biomarker of Neuroprotectant Efficacy in ALS

Abstract: DESCRIPTION (provided by applicant): The objective of this Phase I feasibility study is to develop a reliable biomarker of neuronal damage in a validated mouse model of amyotrophic lateral sclerosis (ALS). Currently, there is no widely accepted biomarker to quantify ALS-induced motor neuron injury. Previously, we have shown that neuronal degeneration in rodents and humans results in cleavage of the cytoskeletal protein MAP-tau. Our laboratory has developed a sensitive ELISA that specifically measures cleaved MAP-tau (C-tau) in rodent models of traumatic brain injury and bacterial meningitis. Using this C-tau ELISA assay, our preliminary studies demonstrate that spinal cord C-tau levels are tenfold higher in late stage symptomatic ALS (G93A-SOD1 mutation) mice as compared to control mice. Using a rotorod motor performance assay, Hensley et al. have recently demonstrated that administration of Nor-dihydroguaiaretic acid (NDGA) to ALS mice delays onset of neurologic deficits. We hypothesize that 1) C-tau is a reliable biomarker of motor neuron injury in ALS mice and 2) C-tau can serve as a screening tool to identify neuroprotectant drags for treating ALS. We will test these hypotheses by determining the relationship between C-tau levels and progression of neurologic deficits in ALS mice. Furthermore, we will test whether the demonstrated neuroprotectant effect of NDGA that delays onset of neurologic deficits in ALS mice also exerts expected effects on C-tau levels. Our Specific Aims are: Specific Aim 1: Compare spinal cord C-tau levels in ALS mice and control mice at 120 days. Specific Aim 2: Determine the relationship between C-tau levels and neurologic deficits in ALS mice as compared to controls. Neurologic deficits and spinal cord C-tau levels will be determined in ALS and age-matched control mice and statistically compared from the presymptomatic stages to late symptomatic stages of disease progression. Specific Aim 3: Determine if C-tau levels reliably quantify the effect of a demonstrated neuroprotectant drag intervention in ALS mice. C-tau levels and rotorod performance will be determined and compared as a function of NDGA treatment.

Thesaurus Terms:
amyotrophic lateral sclerosis, biomarker, neural degeneration, neuroprotectant, tau protein, technology /technique development
neurophysiology, pathologic process, spinal cord
animal tissue, enzyme linked immunosorbent assay

Institution:	PHASE 2 DISCOVERY, INC.
	3130 HIGHLAND AVE, 3RD FL
	CINCINNATI, OH 45219
Fiscal Year:	2003
Department:
Project Start:	15-APR-2003
Project End:	31-MAR-2004
ICD:	NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG:	ZRG1

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