{"id":28,"date":"2008-05-19T13:56:03","date_gmt":"2008-05-19T17:56:03","guid":{"rendered":"https:\/\/www.bumc.bu.edu\/busm-pathology\/busm-faculty-profiles\/j-blusztajn-phd\/"},"modified":"2014-12-10T23:39:46","modified_gmt":"2014-12-11T04:39:46","slug":"j-blusztajn-phd","status":"publish","type":"page","link":"https:\/\/www.bumc.bu.edu\/busm-pathology\/home\/people_main\/j-blusztajn-phd\/","title":{"rendered":"Jan Krzysztof Blusztajn, Ph.D."},"content":{"rendered":"

Professor<\/p>\n

Contact Information<\/h3>\n

Email: jbluszta@bu.edu<\/a>
\nTel. 617-638-4829<\/p><\/blockquote>\n

Education<\/h3>\n

M.S. Molecular Biology; Warsaw University
\nPh.D. Neural and Endocrine Regulation; Massachusetts Institute of Technology<\/p><\/blockquote>\n

Research Interests<\/h3>\n
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Prenatal programming of brain development and aging by essential nutrient availability during gestation<\/h4>\n

We study the effects of perinatal availability of an essential nutrient, choline, on brain development and aging in experimental animals. This research endeavors to determine why it is that supplementation with choline during critical perinatal periods in rats and mice causes a long-term facilitation of visuospatial memory which persists until old age. To this end we are utilizing biochemical, neuroanatomical, and behavioral techniques in a highly unified experimental design. Our studies to date have focused on the development of the basal forebrain cholinergic system, hippocampal MAPK and CREB signaling, and on the developmental patterns of brain gene expression ( Fig. 1<\/strong>). Recent data prompted us to test the hypothesis that the actions of choline are mediated by an epigenetic mechanism involving DNA methylation. Because choline is a donor of metabolic methyl groups its levels modulate the concentrations of cellular S?adenosylmethionine, a compound that serves as a substrate for DNA methylating enzymes. In turn, DNA methylation patterns modulate transcription of multiple genes. These methylation patterns are inherited through cell divisions, providing a possible epigenetic mechanism for modifications in brain gene expression observed many months after the dietary manipulation. Indeed, we found that prenatal availability of choline alters global DNA methylation and patterns of DNA methylation of key genes (e.g. insulin-like growth factor II, Igf2)<\/em> whose expression is known to be regulated by this process. Our data are the first to indicate that choline nutrition in pregnancy alters the epigenome of the brain. Perhaps surprisingly, we observed upregulation of DNA methylation during choline deficiency. We hypothesized that this may be due to induced expression of DNA methylating enzymes by low choline supply. Indeed, choline deficiency increased the expression of DNA methyltransferases, DNMT1 and DNMT3A in brain and liver. These data point to an apparently adaptive epigenomic response to varied gestational choline supply in rat fetal liver and brain. We are vigorously pursuing the testing of the methylation hypothesis [both as it relates to DNA and histones] and we are producing genetic mouse models that help us understand the mechanism of action of choline.<\/p><\/blockquote>\n

\"PKCb2,Fig. 1.<\/strong> Hierarchal clustering of hippocampal mRNA expression microarray data from prenatally choline-supplemented (S), control (C) and choline-deficient (D) rats on postnatal day 18.<\/strong> Arrays and genes were clustered according to the similarity of their expression level to their adjacent neighbor. Red represents high expression and green low expression, relative to mean (black). The results show that the three dietary groups are differentiated from each other. This illustration shows the 303 genes in nine arrays from P18 animals and a magnification of the three genes that were analyzed in subsequent studies: PKC?2, GABABR1, and CAMKII?. See Mellott et al, 2007<\/a><\/span><\/p>\n\n\n<\/tr>\n<\/tbody>\n<\/table>\n

Induction and maintenance of neuronal neurotransmitter phenotype: focus on basal forebrain cholinergic neurons<\/h4>\n

Our second interest is the regulation of the expression of the cholinergic phenotype, i.e. of the genes coding for proteins involved in the synthesis (choline acetyltransferase and choline transporter) and the storage (the vesicular acetylcholine transporter) of the neurotransmitter, acetylcholine (ACh) (Fig. 2<\/strong>). Those studies include molecular biological characterization of the promoter regions of these genes, as well as studies aimed at examining the regulation of their expression during brain development and aging. Our current research focuses on the molecular mechanisms whereby bone morphogenetic protein 9 (BMP9) induce the cholinergic phenotype in neuronal precursor cells. We focus on the basal forebrain cholinergic neurons (BFCN). These cells are important for such functions as learning, memory and attention. We found that BMP9 is expressed in the developing basal forebrain, making it a candidate for an endogenous differentiating factor for BFCN, and possibly also for a maintenance trophic factor for these cells in adulthood. These possibilities are being tested using purified BFCN, isolated by fluorescence-activated cell sorting. The key question that we wish to answer is what are the signaling pathways and transcription factors that allow BFCN to express their cholinergic phenotype.<\/p><\/blockquote>\n

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Fig. 2<\/strong>. Acetylcholine (ACh) is synthesized by choline acetyltransferase (ChAT) that transfers the acetate moiety from acetyl-CoA onto choline. The newly-formed ACh is transported into synaptic vesicles by vesicular ACh transporter (VAChT). Neuronal activity causes exocytosis of ACh into the synaptic cleft where it can interact with postsynaptic receptors to propagate the signal. The muscarinic receptors (mAChR) are G-protein-coupled seven transmembrane domain proteins whereas the nicotinic receptors (nAChR) are ligand-gated ion channels. In order to terminate the action of ACh, intrasynaptic acetylcholinesterase (AChE) hydrolyses it into acetate and choline. Most of the latter is taken up into the presynaptic neuron by choline transporter Cht1 and it is thus recycled for an additional round of ACh synthesis. Illustration and animation by J.K. Blusztajn and P. Kaczmarek<\/span><\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n

See Selected Recent Publications below or Search Additional Publications in MyBibliography<\/a><\/strong>
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