2011 Pilot Projects

2011 Awards

Descriptions and progress of each award can be found in the project details.

Pilot project teams include Hope Center faculty members and others. For more about Hope Center faculty click on their names below.


DNAJB6 in protein aggregation: Integration of clinical material, mouse models and yeast genetics

Principal Investigator: Conrad Weihl (WashU Neurology)
Co-investigators: Heather True (WashU Cell Biology & Physiology), Matt Harms (formerly WashU Neurology)

Project details

Description

Protein aggregation underlies the basis for many degenerative disorders including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis (ALS) and inherited myopathies.  In these diseases, a protein aggregates and then accumulates within selected cellular populations mediating cell death and disease.  Why these aggregates accumulate is unclear however a failure in the proper folding and degradation of cellular protein has been postulated.  Using next generation sequencing of small families with hereditary protein aggregate myopathies in the Washington University Neuromuscular Clinic, we identified mutations in the Hsp40 co-chaperone DNAJB6 as causative in limb girdle muscular dystrophy 1E.  DNAJB6 is an abundant chaperone protein that interacts with aggregate proteins and facilitates their clearance in cell culture.  We propose to use a multi-disciplinary approach to explore the function and dysfunction of DNAJB6 in protein aggregate disorders using yeast genetics, transgenic mouse models and human tissue.

Grants and Awards

“Chaperone Dysfunction in Myopathy: Connecting Yeast Genetics with Mouse Models”
R01 AR068797 (PIs, True-Krob & Weihl)
National Institute of Arthritis and Musculoskeletal and Skin Diseases

“Therapeutic modulation of chaperone function in LGMD1D”
Muscular Dystrophy Association Research Grant (PI, Weihl)

Publications

Stein KC, Bengoechea R, Harms MB, Weihl CC*True HL*.  Myopathy-causing mutations in an Hsp40 chaperone disrupt interactions with specific client conformers. Journal of Biological Chemistry289(30):21120-21130, (2014). *co-corresponding authors.

Bengoechea R, Pittman SK, Tuck EP, True HL, and Weihl CC*. Myofibrillar disruption and RNA binding protein aggregation in a mouse model of limb girdle muscular dystrophy 1D. Human Molecular Genetics. 24(23):6588-602, (2015). *corresponding author

Updated June 2017


Quantitation of Amyloid-β peptides in CSF of Alzheimer’s disease participants by immunoprecipitation/mass spectrometry (IP/MS) and solid phase extraction/mass spectrometry (SPE/MS)

Principal Investigators: Randall Bateman and Anne Fagan (formerly WashU Neurology)

Project details

Description

Alzheimer’s disease (AD) is the most common cause of dementia and is fast approaching epidemic proportions. Biomarkers of underlying disease pathology are being sought to: 1) better understand the pathophysiological processes in AD; 2) to define AD risk; and 3) to evaluate disease-modifying treatment outcomes.

Genetic, biochemical, and animal model studies strongly support the hypothesis that amyloid-beta (Aβ), the primary component of amyloid plaques in AD, plays a central role in the disease process.  Aβ exists as several isoforms that differ in amino acid length and are expressed in different ratios in the central nervous system of healthy individuals.  CSF Aβ42 is decreased by ~50% in individuals with amyloid plaques even before the onset of cognitive symptoms.  Thus, CSF Aβ42 is considered to be a very promising AD biomarker. However, current antibody-based methods for the quantification of Aβ42 differ in their reproducibility and generated values, thus making biomarker standardization efforts a top priority in the field. Furthermore, novel isoforms (Aβ15, 16, 17, 34) have recently been identified and suggest that new pathways in Aβ processing are associated with AD. The relevance of such isoform “signatures” to disease pathogenesis remains to be determined.  The current project proposes to investigate novel and sensitive mass spectometry methods of Aβ isoforms not measured with current antibody-based methods, such as Aβ15, 16, 17, 34, 38, and 43.

Grants and Awards

This work has been extended to the Bateman lab’s current R01 and Zenith awards:

“A Blood Isotope Labeled Amyloid-Beta Test for Alzheimer’s Disease”
Alzheimer’s Association Zenith Award Grant (Institution Grant #3856-80569; PI, Bateman)

“CNS and Plasma Amyloid–Beta Kinetics in Alzheimer’s Disease”
NIH R01NS065667 (PI, Bateman)
Alzheimer’s disease (AD) is the most common cause of dementia and currently has no disease modifying treatments or simple accurate diagnostic tests. The goal of this project is to study how amyloid-beta (a protein thought to cause AD) is made, transported and cleared in the human body. Findings from this study may lead to better treatments for AD.

Publications

Patterson BW, Elbert DL, Mawuenyega KG, Kasten T, Ovod V, Ma S, Xiong C, Chott R, Yarasheski K, Sigurdson W, Zhang L, Goate A, Benzinger T, Morris JC, Holtzman D, Bateman RJ.  Age and Amyloid Effects on Human Central Nervous System Amyloid-Beta Kinetics. ANNALS of Neurology, 10.1002/ana.24454 (2015).

Ovod V, Ramsey KN, Mawuenyega KG, Bollinger JG, Hicks T, Schneider T, Sullivan M, Paumier K, Holtzman DM, Morris JC, Benzinger T, Fagan AM, Patterson BW, Bateman RJ. Amyloid β concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimer’s & Dementia. 2017 Aug;13(8):841-849.


Updated January 2019


Isolating Cell-Type Specific miRNAs from Mice

Principal Investigator: Timothy Miller (WashU Neurology)
Co-investigator: Joseph Dougherty (WashU Genetics)

Project details

Description

Humans have several hundred Micro RNA (miRNAs), which are small, non-coding RNA molecules, each regulating 200-300 genes.  Recent research has suggested that certain miRNAs may both be an exciting biomarker for disease and also a realistic therapeutic target.   In order to better understand miRNA biomarkers and to develop miRNA-based therapies for neurodegeneration, it is important to understand which cells in the body use which of these miRNAs.   To accomplish this, we created a system which labels the miRNAs in one cell type to permit their purification away from the miRNAs of other cells.  We are now generating mouse models with this system which will allow us to study microRNAs in two important cell types for neurological disease – motor neurons and microglia.  The Dougherty Lab has extensive experience creating these types of mouse models and the Miller Lab has extensive experience working with miRNAs.  We will first apply this technology to a disease of motor neurons,  Lou Gehrig’s disease, but anticipate that this system will be useful for other researchers studying other neurodegenerative diseases.

Publications

Hoye ML, Koval ED, Wegener AJ, Hyman TS, Yang C, O’Brien DR, Miller RL, Cole T, Schoch KM, Shen T, Kunikata T, Richard JP, Gutmann DH, Maragakis NJ, Kordasiewicz HB, Dougherty JD, Miller TM. MicroRNA Profiling Reveals Marker of Motor Neuron Disease in ALS Models. J Neurosci.;37(22):5574-5586, (2017).

Reddy AS, O’Brien D, Pisat N, Weichselbaum CT, Sakers K, Lisci M, Dalal JS, Dougherty JD. A Comprehensive Analysis of Cell Type-Specific Nuclear RNA From Neurons and Glia of the Brain. Biol Psychiatry.;81(3):252-264, (2017).


Updated January 2019


Noninvasive white matter histology of living EAE mice

Principal Investigator: Victor Song (WashU Radiology)
Co-investigator: Anne Cross (WashU Neurology)

Project details

Description

Multiple sclerosis (MS) is common, affecting about 0.1% of the US population. It is not feasible to correctly assess the underlying tissue damages or predict the variable course of the disease at present time. Current anti-inflammatory treatments of MS follow a standard dosing regimen. The lack of an effective diagnosis significantly limits the opportunity to adjust the treatment plan according to individual patient responses. By quantitatively distinguishing and tracking inflammation, as well as axon and myelin injury, the proposed diffusion basis spectrum imaging (DBSI) will provide the opportunity to evaluate the effectiveness of treatment in real time.  The goal of the proposed study is to establish a neuroimaging method that can accurately diagnose the extent of neuronal tissue damage in MS. A mouse model of MS, experimental autoimmune encephalomyelitis, will be employed to test DBSI in detecting tissue damage. The success of this study may offer a rare opportunity to improve patient care allowing the modification of the treatment according to individual patient response.

Grants and Awards

“Noninvasive detection and differentiation of axonal injury/loss, demyelination, and inflammation in MS”
Department of Defense Idea Award (PI, Song)

“Noninvasively distinguishing inflammation from tissue injury in optic neuritis”
NIH/NINDS 1R21NS090910-01 (PI, Naismith; MPI, Song)     9/30/14 – 8/31/17

“Understanding the pathophysiology underlying MS progression”
National Multiple Sclerosis Society RG 5258-A-5  (PI, Song)     10/1/14 – 9/30/17

“Biomarkers and Pathogenesis of MS: From Mouse to Human”
NIH/NINDS 2P01NS059560-06A1 (PI, Cross)     7/1/14 – 6/30/19

“Imaging optic nerve function and pathology”
NIH/NEI 1U01EY025500-01 (NEI Audacious Goal Initiative) (PI, Song)     5/1/15 – 4/30/20

“Predictive Value of Diffusion MRI in Cervical Spondylotic Myelopathy”
NIH/NINDS 2 R01 NS047592-10 (Co-PIs, Song and Ray)


Updated July 2017


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