Research Faculty

Address
630 West 168th Street
P&S 12-430
New York, NY 10032

Phone: 212-305-1059
Fax:

lbm2110@cumc.columbia.edu
Education and Training
Columbia University: Postdoctoral Training (2009)
University of Washington: Ph.D. Department of Pharmacology (2006);
B.S./B.S. Biochemistry/Physiological Psychology College Honors (1998)
Laura McIntire, Ph.D.
Assistant Professor of Pathology and Cell Biology
Research Summary

As an Assistant Professor at Columbia University, I have been studying the molecular basis of Alzheimer’s disease (AD) as well as potential therapeutic targets with a focus on lipid biology. Building on my interest of lipid modifying enzymes for my doctoral thesis (2001 – 2006) I was the first to discover and characterize a novel lipid kinase, Multi-substrate Lipid Kinase later renamed Acylglycerol Kinase (MuLK/AGK). For my postdoctoral training (2006 – 2009), I chose to apply my expertise in lipid biology to a clinical application with severe unmet need, determining the role of lipids and lipid modifying enzymes in Alzheimer’s disease (AD). During my time at Columbia University Medical Center (CUMC), which included my postdoctoral training, promotion to Associate Research Scientist (2009) and appointment to Assistant Professor (2014), I have been identifying novel molecules and harnessing their potential as therapeutic targets in AD.

Primarily, I have been interested in the role of lipid modifying enzymes and their potential as therapeutic targets in AD. Synaptojanin 1 (Synj1), a lipid phosphatase which mediates metabolism of the critical signaling lipid, phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2], has been shown to play a role in synaptic vesicle recycling, cytoskeleton maintenance and receptor trafficking in neurons. Our work found that genetic reduction of Synj1 and corresponding maintenance of the PI(4,5)P2, spared synapses from Aβ-triggered dysfunction and loss. In a mouse model of Alzheimer’s disease (Tg2576), PI(4,5)P2 is depleted in a synapse enriched fraction from brain. Genetic reduction of Synj1 both restored PI(4,5)P2 levels and ameliorated behavioral deficits in the Tg2576 mouse model of AD. I’ve found that maintenance of PI(4,5)P2 is critical for synapse maintenance and abrogation of behavioral impairments in a mouse model of the disease (McIntire et al., 2012).

Current work is underway to analyze the signaling pathways and mechanisms of action involved in this rescue and identify other phosphoinositide modifying enzymes which may play a role in maintaining synaptic PI(4,5)P2 using a high content screening paradigm for detection of synapse loss. I also have an interest in identifying small molecules which may be able to modulate PI(4,5)P2 levels using a screening assay I optimized for high throughput screening (HTS) paradigms (McIntire et al., 2014).

To meet the challenges and shortcomings of current cell models for Alzheimer’s disease, I developed a mouse embryonic stem derived neuronal cell model system amenable to high throughput and high content screening of AD phenotypes including Aβ biogenesis and synapse loss (McIntire et al., 2013). I isolated embryonic stem cells from a mouse model of AD and optimized directional differentiation into functional pyramidal neurons, the most vulnerable cell population in AD. I’ve conducted a mid-throughput screen of a compound library of small molecules with history of use in the human pharmacopeia or in clinical trials. This screening platform is currently used for high-content screening for abrogation of amyloid β-peptide-triggered synapse loss using CRISPR. Coordinating both the use of neuronal mESN and my interest in phosphoinositide lipids, I propose to use CRISPR technology to target phosphoinositide metabolism, an emerging and highly promising target in AD.

This research is uniquely suited for my expertise in identifying and validating novel cellular pathways as potential future therapeutic targets in AD. I have expertise in lipid biology, mouse models of Alzheimer’s disease as well as screening assay development and implementation and mechanistic neuroscience required for the successful completion of these studies. I am personally dedicated to discovering the role of novel cellular targets in AD pathogenesis and pharmacologically harnessing them for amelioration of this devastating disease.
Selected Publications

Chun, YS; Kwon, OH; Oh, HG; McIntire, LB; Kim, TW; Park, Myoung K; Chung, S. (2015) O-GlcNAcylation of amyloid-β precursor protein at T576 regulates trafficking and processing. J. Biochemical and Biophysical Research Communications Nov 27;467(4):955-60.

McIntire LB, Lee KI, Chang-Ileto B, Di Paolo G, Kim TW. (2014) Screening assay for small-molecule inhibitors of synaptojanin 1, a synaptic phosphoinositide phosphatase. J Biomol Screen. Apr;19(4):585-94.

McIntire LB, Landman N, Kang MS, Finan G, Hwang J, Moore AZ, Park L, Lin CS, Kim T-W. Phenotypic assays for β-amyloid in mouse embryonic stem cell-derived neurons. (2013) Phenotypic assays for β-amyloid in mouse embryonic stem cell-derived neurons. Cover Article of Chemistry & Biology – Cell. July 25;20(7):956-967.

McIntire LB*, Berman D*, Myaeng J, Staniszewski A, Arancio O, Di Paolo G and Kim, T-W. *equal contribution. (2012) Reduction of Synaptojanin 1 ameliorates synaptic and behavioral impairments in a mouse model of Alzheimer's disease. Journal of Neuroscience. Oct 31;32(44):15271-6.

Berman DE, Dall’Armi C, Zhang H, Moore AZ, Voronov SA, McIntire LB, Cremona O, Arancio O, Kim T-W, Di Paolo G. (2008) Oligomeric amyloid-beta peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism. Nature Neuroscience. May;11(5):547-554.

Epand RM, Shulga YV, Timmons HC, Perri AL, Belani JD, Perinpanathan K, Johnson-McIntire LB, Bajjalieh S, Dicu AO, Elias C, Rychnovsky S, Topham MK. (2007) Substrate Chirality and Specificity of Diacylglycerol Kinases and the Multisubstrate Lipid Kinase. Biochemistry. Dec 11;46(49):14225-14231.

Waggoner DW, Johnson LB, Mann PC, Morris V, Guastella J, Bajjalieh SM. (2004) MuLK, a novel eukaryotic multi-substrate lipid kinase. Journal of Biological Chemistry. Sep 10;279(37):38228-35.

Figlewicz DP, Patterson TA, Johnson LB, Zavosh A, Israel PA, Szot P. (1998) Dopamine transporter mRNA is increased in the CNS of Zucker fatty (fa/fa) rats. Brain Research Bulletin. Jun; 46(3):199-202.

Current Projects

Currently, I’ve been pursuing the validation of putative AD drug targets by investigating mechanism of action and in vivo studies. I’ve identified a novel target of a CNS active compound class identified in a small molecule screen using an in vitro, cell based assay for β-site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) regulators. I continue to validate hits which is the subject of a Mentored Research Scientist Development Award (K01, 2014-2019).

Honors and Awards

2009
Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, Alzheimer’s Disease Research Center, Pilot Grant, Columbia University

2010
Irving Institute for Clinical and Translational Research, Pilot Grant, Columbia University

2010
Alzheimer’s Association New Investigator Research Grant (NIRG)

2014
Exploratory/Developmental Research Grant R21, NIH, NINDS

2014
Mentored Research Scientist Development Award K01, NIH, NIA

2015
Best Abstract Award for Invited Platform Presentation– Columbia University Pathology and Cell Biology Translational Research Retreat

2016
Alzheimer’s Association New Investigator Research Grant (NIRG)

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