Dr. Paul and team
The Paul Laboratory studies the fundamental disease biology of Alzheimer's disease with the ultimate goal of translating this understanding to the discovery and development of disease-modifying therapies. The work in our laboratory is multifaceted and involves very basic cellular-molecular studies using a variety of cell-based in vitro models (both of neurons and glia) as well as in vivo work involving the creation and characterization of a number of transgenic mouse models of Alzheimer's disease-related neuropathology. Read more
The role of Hsp90 in Alzheimer’s disease
National Institutes of Health/National Institute on Aging Grant
The overall objective is to provide new therapeutic strategies for AD treatment. Based on our preliminary data, our studies demonstrate that Hsp90 binds to mutant APP and regulates its metabolism. Therefore, we hypothesize that Hsp90 is critical in dysregulated APP processing and modulates the progression of AD. We characterize the regulatory roles of Hsp90 in amyloid generation by investigating the dynamic Hsp90-APP interaction and its impact on APP processing/trafficking. Then finally, the therapeutic effects of Hsp90 inhibitors will be determined in a mouse model of AD.
Genomic analysis of bipolar disorder in a genetic isolate (NIH/NIMH R01 Grant)
National Institutes of Health/National Institute of Mental Health Grant
To identify and fully elaborate genetic variants that underlie the susceptibility to develop a highly heritable form of mental illness, bipolar affective disorder in a well-studied and phenotyped genetic isolate, the Old Order Amish.
Treatments for Alzheimer’s disease
Johnson & Johnson Pharmaceuticals
To discover a human or humanized anti-tau monoclonal antibody which recognizes a pathological tau conformation (s) and readily blocks the propagation of misfolded tau protein in vivo and the resulting neurodegeneration and disease progression which characterizes Alzheimer’s disease (AD).
Apolipoprotein E biology in Alzheimer's disease
To advance our fundamental knowledge of the role apoE plays in the etiology and pathogenesis of AD, i.e. in order to delineate one or more novel drug targets for potentially treating and (or) preventing AD.
Gene delivery of apolipoprotein E2 as a treatment for Alzheimer's disease
Alzheimer’s Drug Discovery Foundation (ADDF)
To quantify the effects of apoE2 expression on brain Aβ/amyloid burden by comparing the effects of both intracerebral as well as intraventricular gene delivery of apoE2 using two viral vectors (AAV2 and lentivirus) on apoE2 expression and brain amyloid burden in the PDAPP mouse model of Alzheimer’s disease.
In this project we extended our earlier studies on apoE2 gene delivery as a potential treatment strategy for AD by using an optimized and well-studied viral vector(s) and exploring relatively non-invasive routes of CNS administration. Specifically, we will explore the utility of the Rhesus serotype adeno-associated viral vector (AAVrh.10) and two different delivery approaches or routes of administration (e.g. direct intracerebral/intraparenchymal and intracisternal) in mice (using a new and more relevant transgenic AD mouse model) to facilitate an eventual clinical trial of apoE2 gene delivery in AD patients.
Investigating the role of microglia in tau clearance in Alzheimer's disease
Coins for Alzheimer's Research Trust (CART)
This project focuses on characterization of the cellular pathways and regulatory mechanisms involved in tau clearance by microglia. The data generated from this study will help address several fundamental questions regarding tau clearance by microglia and will provide novel therapeutic interventions for treating Alzheimer's disease by targeting a microglial-mediated tau clearance pathway.
Effect of APOE on CNS Neurons: Role of LRP
National Institute of Neurological Disorders & Stroke (NINDS)
This research project is aimed at investigating several aspects of the "disease biology" of Alzheimer's disease (AD) with an overall goal of developing disease-modifying therapies to treat or prevent AD. This is accomplished by using a variety of transgenic mouse models of AD pathology shown to have apoE isoform-dependent effects on brain amyloid deposition/burden (apoE4>apoE3>>apoe2) in aging mutant APP transgenic mice. This approach closely recapitulates what is observed in humans who have high genetic risk (apoE4 carriers) for AD (measured by PET imaging).
Dr. Petsko and team.
During the past 10 years, Dr. Petsko has pursued groundbreaking research not only on how proteins work, but how they are related to the causes of neurodegenerative diseases. Using the techniques of genetics, structural biology, and structure-guided drug discovery, his laboratory is able to identify, validate, and exploit novel targets for the treatment of age-related neurodegenerative disorders such as Alzheimer’s, Parkinson’s, and Lou Gehrig’s diseases. Read more
Stabilization of alpha-synuclein as therapeutic strategy for Parkinson's disease
The Michael J. Fox Foundation for Parkinson’s Research Grant
The overall objective of this grant is to complete the NMR structure determination of a new, tetrameric form of alpha-synuclein discovered in this lab and repeat the structure determination for one or more of the Parkinson’s Disease-associated mutants of the protein. It is further proposed to verify that this form exists in neurons and that the ratio of this form to that of the fibrilar form of the protein changes with the inset and progression of Parkinson’s Disease, thereby validating stabilization of the tetramer as a novel approach to the prevention of the disease, and to develop inhibitors to block the proteolytic processing of the protein.
Mechanisms of Enzymic Proton and Hydride Transfers
National Institutes of Health/National Institute of General Medicinal Sciences Grant
The overall objective of this project is to use time-resolved and other forms of protein crystallography to achieve an understanding of the structural basis for efficient enzymic catalysis of hydrogen transfer from weakly acidic carbon and oxygen centers.
The Role of FUS/TLS in Familial Amytrophic Lateral Sclerosis by Studies in a Model Organism
ATA - The ALS Therapeutic Alliance
The overall objective of this proposal is to develop a system in a model organism that permits genetic and biochemical studies of the role of the protein FUS/TLS in the neurologic disease ALS, and to exploit that system both for such studies and as a vehicle for high-throughput screening for drugs that may ameliorate FUS/TLS-induced cytotoxicity. In parallel, studies of the structure of FUS/TLS will be carried out with the aim of using in silico screening to find drugs that will stabilize the nuclear-bound form of the protein.
High Throughput Screening for Compounds to Mitigate Toxicity of FUS/TLS & SOD1
National Institutes of Health
The goal of this project is to identify compounds that suppress the toxicity fo fUS/TLS to motor neurons, and to find small molecules that either stabilize the dimeric form of superoxide dismutase or lower its expression in the central nervous system.
New Approaches to the Prevention and Treatment of Neurologic Disorders
Fidelity Biosciences Research Initiative (FBRI)
The overall objective is to identify, functionally characterize, and exploit new targets for the prevention and treatment of several neurologic disorders, with emphasis on Alzheimer’s, Parkinson’s and Lou Gehrig’s diseases.