Associate Provost for Research Boston University Medical Campus
NINDS - National Institute of Neurological Disorders and Stroke	Research Resources

Abstract

Abstract: DESCRIPTION (provided by applicant): Degeneration or malfunction of central and peripheral cholinergic neurons underlies and/or contributes to the pathophysiology of a variety of disorders including Alzheimer's Disease, Motor Neuron Disorders, and Familial Dysautonomias, and possibly memory loss associated with aging. Understanding the cholinergic phenotype and the mechanisms regulating it is crucial to the development of experimental approaches to study these diseases, and to the design of treatment strategies. We have focused on the elucidation of mechanisms that regulate the cholinergic neurotransmitter phenotype and our data show that specific bone morphogenetic proteins (BMPs) dramatically upregulate the expression of this phenotype in primary cultures of mouse central nervous system, and in the brain in vivo. The cellular and molecular mechanisms of action of BMPs in inducing and maintaining the neuronal cholinergic phenotype remain unknown and will be the subject of the current proposal. Specifically we propose: 1. To identify the intracellular signaling molecules that mediate the induction of the cholinergic phenotype by BMPs, and 2. To delineate the promoter regions within the cholinergic gene locus that respond to BMPs and to identify protein transcription factors that bind to those BMP-responsive regions. The studies will be performed on primary neuronal cultures obtained from wild type mice and from animals with targeted mutations of genes encoding candidate transcription factors that may mediate the effects of BMPs on the cholinergic phenotype. Investigations will focus on the signaling functions of Smad proteins and other transcription regulators, expression of cholinergic-specific promoters in reporter constructs, and DNA binding of candidate transcription factors. In addition, we propose animal studies to test the hypothesis that administration of BMPs in vivo can correct septo-hippocampal lesion evoked downregulation of cholinergic function using neuroanatomical tools. Taken together this research will provide basic and preclinical data on the mechanisms of action of BMPs in the brain and the potential for their use in treating neurological disorders affecting cholinergic neurons.

Thesaurus Terms:
bone morphogenetic protein, central nervous system, gene expression, genetic promoter element, protein structure function, transcription factor
acetylcholine, binding site, brain disorder, gene mutation, intracellular transport, ligand, neuron, phosphorylation, protein transport, receptor binding
cell line, gel mobility shift assay, gene targeting, genetically modified animal, immunocytochemistry, immunoprecipitation, northern blotting, tissue /cell culture, western blotting

Institution:	BOSTON UNIVERSITY MEDICAL CAMPUS
	715 ALBANY ST, 560
	BOSTON, MA 021182394
Fiscal Year:	2004
Department:	PATHOLOGY AND LABORATORY MEDICINE
Project Start:	01-JUN-2002
Project End:	31-MAY-2006
ICD:	NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
IRG:	MDCN