Jin-Moo Lee, M.D., Ph.D.

Norman J. Stupp Professor
Cerebrovascular Disease Section

Neurosciences Program

  • 314-747-1138

  • 314-362-9461

  • 314-362-9462

  • 8111

  • BJC Institute of Health, Rm 9606

  • leejm@wustl.edu

  • http://jmleelab.wustl.edu/

  • amyloid, apoptosis, Alzheimer’s disease, hypoxia, hypoxia-ischemia, ischemia

  • Pathogenesis of amyloid fibrils and amyloid plaques in AD mouse models

Research Abstract:

Our lab is interested in several exciting research projects spanning in vitro studies in cell culture, in vivo studies in animal models of disease, and clinical studies using data from human patients.

1. Cellular Processing of APP in Alzheimer’s Disease (AD): AD is characterized by the deposition of extracellular plaques comprised of primarily of the amyloid beta peptide (Aβ), a peptide derived from serial proteolytic cleavages of the Amyloid Precursor Protein (APP). We study the cellular and molecular mechanisms of Aβ generation, aggregation, clearance, and deposition as plaques. In particular, we have developed a novel technique using fluorogenic click chemistry and advanced microscopy techniques in live cells to visualize APP proteolysis and subsequent Aβ generation, and their respective trafficking itineraries. We hypothesize that the earliest aggregates of Aβ form intracellularly in the endosome-lysosome system, prior to plaque development.

2. Neuroplasticity after stroke: Ischemic stroke is a leading cause of disability that directly damages the circuitry of the brain. There is a great need for precision medical therapies to increase plasticity and recovery in human patients. We use mouse models of stroke to study the central mechanisms underlying plasticity in the brain after injury, and how they can be targeted with gene therapy. We collaborate with several groups in the Radiology department and use novel optical neuroimaging techniques and electrophysiology to measure the connectivity of brain networks and how they are affected by injury and therapy.

3. Genetic influences on early outcomes after acute ischemic stroke: We use genome-wide-association studies to identify genetic variants, genes, and pathways implicated in brain injury mechanisms after acute ischemic stroke. Using a variety of phenotypes, including clinical and neuroimaging quantitative endophenotypes, we are interested in understanding the underlying genetic architecture of primary and secondary brain injury. By finding genetic loci associated with these phenotypes, we hope to identify potential targets for therapeutic intervention to attenuate brain injury after ischemia.

4. Pathophysiology of Cerebral Small Vessel Disease and Vascular Dementia: Using advanced MR imaging, we are measuring cerebral blood flow (CBF) and oxygen metabolism in young and aged subjects with and without cerebral small vessel disease (CSVD). We are testing the hypothesis that white matter hyperintensities (WMHs) are caused by chronic ischemia due to CSVD, and that the precise spatial pattern of WMHs may indicate different underlying CSVDs.

Selected Publications:

Mitra A, Kraft AW, Wright P, Acland B, Snyder A, Czerniewski L, Rosenthal Z, Snyder L, Culver J, Lee J-M, Rahcle M, Distinct temporal and laminar relationships in spontaneous infra-slow brain activity. Neuron, 2018, 98(2):297-305.

Kraft AW, Bauer AQ, Culver JP, Lee J-M. Sensory Deprivation Following Focal Ischemia Accelerates Remapping and Behavioral Recovery through Arc-Dependent Synaptic Plasticity. Sci Transl Med, 2018, Jan 31;10(426).

Kraft AW, Mitra A, Bauer AQ, Snyder AZ, Raichle ME, Culver JP, Lee JM. Visual experience sculpts whole-cortex spontaneous infraslow activity patterns through an Arc-dependent mechanism. Proc Natl Acad Sci U S A. 2017 Nov 14;114(46):E9952-E9961

Bauer AQ, Kraft AW, Baxter GA, Wright PW, Reisman MD, Bice AR, Park JJ, Bruchas MR, Snyder AZ, Lee JM, Culver JP. Effective Connectivity Measured Using Optogenetically Evoked Hemodynamic Signals Exhibits Topography Distinct from Resting State Functional Connectivity in the Mouse. Cereb Cortex. 2017 Nov 9:1-17.

Hu X., Crick S.L., Bu G., Frieden C., Pappu R.V., Lee J.-M. Amyloid seeds formed by cellular uptake, concentration, and aggregation of the amyloid-beta peptide, Proc Natl Acad Sci USA, 106(48):20324-9, 2009.

Zhang R., Hu X., Khant H., Ludtke S.J., Chiu W., Schmid M.F., Frieden C., Lee J.-M., Inter-protofilament interactions between Alzheimer’s Aβ1-42 peptides in amyloid fibrils revealed by cryo-EM, Proc Natl Acad Sci USA, 24:106(12):4653-8, 2009.

Yan P., Bero A., Cirrito J.R., Xiao Q., Hu X., Wang Y., Gonzales E., Holtzman D.M., Lee J.-M., Characterizing the appearance and growth of amyloid plaques in APP/PS1 mice, J Neurosci, 29(34):10706-14, 2009.

Malik et al. NINDS Stroke Genetics Network (SiGN); MEGASTROKE Consortium, Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes. Nat Genet. 2018 Apr;50(4):524-537.

NINDS Stroke Genetics Network (SiGN); International Stroke Genetics Consortium (ISGC). Loci associated with ischaemic stroke and its subtypes (SiGN): a genome-wide association study. Lancet Neurol. 2015 Dec 18

Chen Y, Dhar R, Heitsch L, Ford A, Fernandez-Cadenas I, Carrera C, Montaner J, Lin W, Shen D, An H, Lee JM. Automated quantification of cerebral edema following hemispheric infarction: Application of a machine-learning algorithm to evaluate CSF shifts on serial head CTs. Neuroimage Clin. 2016 Sep 26;12:673-680.

Dhar R, Yuan K, Kulik T, Chen Y, Heitsch L, An H, Ford A, Lee JM. CSF Volumetric Analysis for Quantification of Cerebral Edema After Hemispheric Infarction. Neurocrit Care. 2015 Oct 5.

Guilliams KP, Fields ME, Ragan DK, Eldeniz C, Binkley MM, Chen Y, Comiskey LS, Doctor A, Hulbert ML, Shimony JS, Vo KD, McKinstry RC, An H, Lee J-M, Andria L. Ford. Red cell exchange transfusions lower cerebral blood flow and oxygen extraction fraction in pediatric sickle cell anemia. Blood, 2017, Dec 2;17:717-730..

Fields ME, Guilliams KP, Ragan DK, Binkley MM, Eldeniz C, Chen Y, Hulbert ML, McKinstry RC, Shimony JS, Vo KD, Doctor A, An H, Ford AL, Lee J-M. Regional Oxygen Extraction Predicts Border Zone Vulnerability to Stroke in Sickle Cell Disease. Neurology, 2018, Mar 27;90(13):e1134-e1142.

Dhand A, Luke DA, Lang CE, Lee JM. Social Networks and Neurological Illness. Nat Rev Neurol. 2016 Oct; 12(10):605-12

Lee J.-M., Zipfel G., Choi DW. The changing landscape of ischaemic brain injury, Nature, 399:A7-14, 1999.

Lee J.-M., Grabb M.C., Zipfel G.J., Choi D.W. Brain tissue response to ischemia, J Clinical Investigation, 106(6):723-731, 2000.

Last Updated: 5/7/2018 11:38:50 AM

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