Taub Institute: Genomics Core
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Featured Research

October 2015

Andrew Sproul, PhD

Stem Cell and Cellular Models Platform Update
The Stem Cell and Cellular Models Platform was created in order to facilitate the use of human biological model systems throughout the Taub research community. Directed by Dr. Andrew Sproul, the Platform provides disease-specific human stem cell lines, either by using genome-editing to introduce mutations into a control backbone hESC or iPSC line, or by reprogramming patient material. This approach allows the construction of isogenic cell line libraries that will be shared with the entire Taub community. The Platform also differentiates stem cell lines to disease-relevant cell types such as forebrain cortical neurons. In order to facilitate use of the Platform, the Innovation Grants program has launched in order to provide subsidized service to generate preliminary grant data.
For more information, please email Platform Director Andrew Sproul, PhD, aas2003@cumc.columbia.edu.

Brain Imaging Analysis Platform Update
The capability to design, acquire, analyze, and interpret data from brain imaging studies in both humans and animals requires specialized skills and software applications that heretofore have been limited to individual grants. The Brain Imaging Analysis Platform was created to encourage and enable Taub investigators, particularly those who may never have considered imaging previously, to utilize such expertise to further their work in the Taub Institute. This Platform is bolstered by Columbia University's extensive, recent investments in the latest generation of imaging apparatus across the University. This apparatus can enable Taub lab groups to routinely correlate their physiological, biochemical, and clinical data with changes in brain structure and brain metabolism in a rapid and efficient manner. Thus far, the Platform has awarded "seed funding" for five human studies and one animal model, with more still to be awarded. Platform Co-Directors Drs. Scott Small and Yaakov Stern strongly encourage all Taub investigators to think broadly about how imaging might further their research, and to contact them for guidance on matching their research question to all available imaging modalities.
For more information, please email Platform Co-Directors Scott Small, MD, sas68@cumc.columbia.edu and/or Yaakov Stern, PhD, ys11@cumc.columbia.edu.

Patient Oriented Research Platform Update
The goal of the Patient Oriented Research Platform, directed by Dr. Karen Marder, is to increase the recruitment and retention of study participants by developing a more efficient recruitment process and making research studies more easily accessible to interested participants. Research Nurse Coordiantor Betina Idnay, RN was hired to play a key role in the implementation of this Platform. She will serve as a liaison with the research teams and will educate patients and volunteers seen Taub's Division of Aging and Dementia and Division of Cognitive Neuroscience clinical practices, to inform them about participation in both observational studies and clinical trials at the Taub Institute. From June 2015 through September 2015, 1370 electronic medical records of the patients seen by Taub clinicians in these divisions were prescreened, 271 (20%) patients were potentially eligible to participate in research. Out of these 271 patients, 61 (23%) were referred to Research Nurse Coordinator Betina Idnay, and 6 (10%) of those were enrolled in a study. Moving forward, we will try to maximize recruitment into ongoing trials by referring participants from the community who are not eligible for a specific trial to Ms. Idnay to discuss other trials that they may be interested in. We will also assist principal investigators in their study design before grant submission by providing insight of the target study participants seen in the practice and from outside referrals.
For more information, please email Research Nurse Betina Idnay at bsi2102@cumc.columbia.edu.

Update on Clinical Trials in AD and Other Conditions
A number of Taub physician-scientists are involved in important clinical drug study trials on Alzheimer's disease and related disorders, including symptomatic or pre-symptomatic, mild cognitive impairment, progressive supranuclear palsy, and Huntington's disease. These physician-scientists include Drs. Karen Bell, Lawrence Honig, Sarah Janicki, William Kreisl, and Karen Marder. Alzheimer's disease and related neurodegenerative disorders are the subject of a wide-range of rationally-designed clinical trials of various agents to intervene in the degenerative process. Beta-amyloid is central to the development of Alzheimer's disease, therefore, a number of trials are designed to decrease production or increase clearance of this abnormal peptide. Beta secretase inhibitors are under investigation to decrease production, and passive as well as active immunization trials are ongoing to reduce amyloid levels in the brain. There are also trials of agents to decrease neuronal injury or impede the tau changes in Alzheimer's disease. The full spectrum of clinical trials including phase 0, 1, 2, 3, and 4 trials was discussed, as well as the considerable resources required in terms of highly trained personnel to accomplish these important, multicenter, human clinical investigations to alleviate the progression and burden of this disorder of memory and cognition.
For more information, please email Lawrence Honig, MD, PhD, lh456@cumc.columbia.edu.

Nicole Schupf, PhD, Dr. PH

Down Syndrome and Alzheimer Disease: Biomarkers of Risk
By age 40 years, all individuals with Down syndrome (DS) show the neuropathological changes of AlzheimerÔÇÖs disease (AD) and have a high risk for dementia. The increased risk for dementia in adults with DS has been attributed to triplication and overexpression of the gene for amyloid precursor protein (APP), located on chromosome 21. However, there is a wide range of age at onset of dementia, suggesting the importance of other risk factors and little is known about the biomarkers that may predict clinical onset. We have examined individual differences in A╬▓ peptide levels, genetics of A╬▓ peptide level and rate of change, and genetic variants associated with age at onset and risk of AD in adults with DS. Our current work is focused on a comprehensive examination of biomarkers including the relationships between levels and rates of change in blood based biomarkers such as ╬▓-amyloid peptides, protein, inflammatory and lipid profiles, measures of amyloid and tau concentration in cerebrospinal fluid, neuroimaging-based changes (MRI and PET) and genetic polymorphisms influencing these biomarkers. Relationships among demographic, cognitive, clinical, blood based and CSF biomarkers, imaging measures, and genetic variants will be examined to develop the most valid indicators of preclinical and early stages of AD. Study of biomarkers for early dementia changes may yield critical data documenting the transition from normal aging to mild cognitive impairment to clinical dementia in individuals with DS. This can provide key insights into the pathways involved in AD onset and may allow for future therapeutic interventions before irreversible cognitive deterioration has occurred.
For more information, please email Nicole Schupf, PhD, Dr. PH, ns24@cumc.columbia.edu.

Building an Interdisciplinary Research Agenda for Addressing Racial/Ethnic Disparities in Alzheimer's Disease and Cognitive Aging
Taub Institute investigators have demonstrated leadership and innovation in investigating racial/ethnic disparities in cognitive aging and Alzheimer's disease (AD), and now that the NAPA legislation has focused new attention on AD disparities, we are well suited to continue to advance science and address major research gaps in this area. We have found that clinic-based studies of racially and ethnically diverse people are subject to significant sampling bias and methodological limitations and, therefore, are not suitable for research on disparities in AD. Another important finding is that indicators of school quality account for racial disparities in AD incidence and cognitive decline. In addition, biological, environmental, behavioral, and sociocultural mediators of disparities have been identified, and necessitate interdisciplinary, lifecourse approaches for determination of causal mechanisms of AD disparities.
For more information, please email Jennifer Manly, PhD, jjm71@cumc.columbia.edu.

Andrew Teich, MD, PhD

A Systems Approach to Understanding Molecular Drivers of Disease in AD
Our lab is leveraging new techniques to analyze Next-gen sequencing data to discover new targets for therapeutic intervention in Alzheimer's disease (AD). We are starting with brain tissue from human patients, and we are sequencing RNA (RNA-seq) and will soon begin sequencing of methylated DNA (bisulfate sequencing) as well as other analysis that detect higher-order DNA interactions (Hi-C). In all of these efforts, we are interested in how genome expression is dysregulated in AD. With this vast amount of information, we are employing a variety of analytic techniques to zero in on how this dysregulation may impair synaptic function, and how synaptic function my be saved. Validation of our targets in culture is ongoing, and we have several promising candidates under investigation.
For more information, please email Andrew Teich, MD, PhD, aft25@cumc.columbia.edu.

The Role of the Blood-Brain Barrier in Neurological Disorders: Lessons from Animal Models of Stroke and Multiple Sclerosis
Brain endothelial cells form a paracellular and transcellular barrier to blood-borne solutes via tight junctions (TJs) and scarce endocytotic vesicles. The blood-brain barrier (BBB) plays a pivotal role in the healthy Central Nervous System and its breakdown is a hallmark of many neurological disorders including ischemic stroke and multiple sclerosis. To understand the mechanisms of BBB dysfunction in neurological disorders, we have generated reporter mice where tight junctions or caveolae at the BBB are labeled with fluorescent proteins and we have performed an in vivo analysis of dynamic structural and functional barrier changes in live anesthetized mice. Using this approach we have discovered that a stepwise impairment in transcellular followed by paracellular pathways contributes to BBB dysfunction in ischemic stroke. We have recently investigated the mechanisms of BBB impairment in MOG35-55 Experimental Autoimmune Encephalomyelitis (EAE), an animal model for multiple sclerosis (MS) to assess whether these changes mimic those observed during BBB disruption in ischemic stroke. We have found that dynamic changes in TJs occur from the onset and throughout the disease, whereas transcytosis increases at the peak of clinical disease. These findings suggest that TJ disruption is necessary for the onset of EAE, whereas transcellular permeability enhances disease severity. Moreover, the kinetics of paracellular versus transcellular impairment in BBB function is quite different between ischemic stroke and multiple sclerosis.
For more information, please email Dritan Agalliu, PhD, da191@cumc.columbia.edu.

Novel Regulation and Therapeutic Intervention for Retinal Edema
Our laboratory studies the regulation and function of caspases in the adult nervous system, both dissecting molecular mechanisms and providing targets for therapeutic intervention. Our studies of cerebral ischemia show that caspase-9 regulates neuronal death post-ischemia and we have now elucidated a novel function of caspase-9 in the regulation of vasogenic edema. To facilitate this work we developed a specific cell permeant inhibitor of caspase-9 that can be delivered intranasally to provide protection out to 3 weeks post-ischemia. We now propose that caspase-9 regulates edema in other pathologies of the nervous system and have begun to study the function of caspase-9 in models of diabetic macular edema, a major cause of new blindness in people under the age of 50.
For more information, please email Carol Troy, MD, PhD, cmt2@cumc.columbia.edu.

Investigating the Role of Epha1 in Alzheimer's Disease
Long studied in the context of cancers, Eph receptors are increasingly recognized as key players in various neurological disorders, ranging from ALS to Alzheimer's disease (AD). One member of this large family of receptor tyrosine kinases, EphA1, was recently identified through genome-wide association studies (GWAS) as a risk factor for late onset AD (LOAD). Moreover, a rare coding variant in EphA1 was recently identified in LOAD patient, supporting a causative role. However the biological impact of EphA1 on the disease are not understood. Here, we present the preliminary results of a series of studies designed to investigate the role of EphA1 and its variants in AD pathogenesis, with a particular focus on synaptic dysfunction, an early occurrence in AD.
For more information, please email Roger Lefort, PhD, rl2040@cumc.columbia.edu.

Impact of AD Pathology on Entorhinal Cortex
In Alzheimer's disease (AD) memory impairment is severe with trouble remembering familiar locations and navigating around them, symptoms that appear very early in the disease. This spatial disorientation is thought to result from dysfunction in a circuit known as the entorhinal cortex-hippocampal (EC-HPC) circuit. To better understand the properties of neurons in this circuit in an AD mouse model, we examined the firing properties of the EC neurons called "grid cells" that fire in a grid-like pattern along the animal's entire environment and the HPC neurons called "place cells" that fire in a specific location in an animal's environment. Both grid and place cells, part of animal's mental representation of space, are known to be affected in Tau and Abeta mouse models of AD. We are currently investigating the mechanism underlying this spatial dysfunction.
For more information, please email S. Abid Hussaini, PhD, sah2149@cumc.columbia.edu.


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