2012 Pilot Projects

Description

Brain injury is a leading cause of death and disability in the United States.  Sudden brain injury usually takes one of two forms: traumatic or vascular.  Traumatic brain injury occurs when the head receives a severe external impact, possibly from an improvised explosive device, a car windshield, or even a barreling linebacker.  Victims of such events may develop brain damage near the site of impact, such as brain contusions, as well as diffuse brain injuries resulting from ripple effects of the impact.  The axons that make up the brain’s wiring are especially susceptible to such ripple effects, and diffuse axon injury may be the most important consequence of brain trauma.

Vascular brain injury takes the form of vascular blockage, causing strokes, and the far more deadly vascular rupture, which causes brain hemorrhages.  Hemorrhagic brain injury frequently results in coma and long-term cognitive and emotional impairment, both of which are likely caused by diffuse brain damage.  Although an enlarging bleed causes obvious injury to nearby brain tissue, very little is known about how hemorrhages impact the brain diffusely.  New results from our group indicate that axon injury, so crucial in traumatic brain injury, also occurs during hemorrhagic brain injury.  Our research is aimed at exploring this connection through the use of advanced brain imaging techniques available both in the laboratory and in the clinical setting.  We hope to define a new class of brain injury—vascular traumatic brain injury—thereby connecting the large body of research into traumatic brain injury to a vascular disease process of particular relevance to our aging population.  We believe that this framework will lead to new diagnostic and prognostic tests for victims of brain trauma, and help generate new targeted therapies.

Grants and Awards

“Advanced diffusion biomarkers of brain injury in subarachnoid hemorrhage”
NIH K08 NS 094860 01 (PI, Kummer)
The key to improving outcomes after subarachnoid hemorrhage lies in improving our understanding of how it damages the brain. Unfortunately a great deal of apparent brain injury goes undetected with conventional imaging studies. Therefore, we seek to develop new imaging parameters linked to defined pathologies that can be used to diagnose and monitor brain injury after subarachnoid hemorrhage, tie these pathologies to the outcomes of greatest relevance to patients, and ultimately target them with novel treatments.

“An MRI fingerprint of synapse loss in AD”
BrightFocus Foundation (PI, Kummer)

Publications

Kummer, Terrance T., Sandra Magnoni, Christine L. MacDonald, Krikor Dikranian, Eric Milner, James Sorrell, Valeria Conte, Joey J. Benetatos, Gregory J. Zipfel, and David L. Brody. Experimental Subarachnoid Haemorrhage Results in Multifocal Axonal Injury. Brain 138, no. 9: 2608–18, (2015).

Fanizzi, Claudia, Andrew D. Sauerbeck, Mihika Gangolli, Gregory J. Zipfel, David L. Brody, and Terrance T. Kummer. Minimal Long-Term Neurobehavioral Impairments after Endovascular Perforation Subarachnoid Hemorrhage in Mice. Scientific Reports 7, no. 1 (August 8, 2017): 7569.

Updated January 2019

Description

Niemann-Pick C1 disease is a progressive pediatric neurodegenerative disease for which there are no FDA-approved therapies. Mutations in the Niemann-Pick C1 (NPC1) gene are responsible for most cases of the disease, which is characterized by abnormal accumulation of cholesterol in brain cells. Recent studies have shown that the most prevalent disease causing mutation results in an NPC1 protein that is misfolded and, as a consequence, is rapidly degraded and therefore not delivered to the proper site within the cell. For this pilot project, we will test whether reducing the levels of a cellular quality control protein will increase the levels of the mutant NPC1 protein, reduce cholesterol storage, and improve brain cell function. These experiments will be performed in a new genetically engineered mouse developed at Washington University that expresses the NPC1 mutation that causes human disease. Information learned from these studies may lead to development of treatments for this devastating disease.

Grants and Awards

“A Phase 1 Dose Escalation Study of Vorinostat in Niemann-Pick C1 Disease”
NIH/NICHD U01HD079065-01 (PI, Ory)
The goal of this study is to develop a Phase 1, first-in-human, open-label, single-center, dose escalation study of Vorinostat in late adolescents and adults with NPC1 disease to establish the safety of Vorinostat for treatment of this disorder.

“Proteostatic regulation for treatment of NPC1 disease”
Ara Parseghian Medical Research Fund (PIs, Ory, Maxfield, Walkley)

“Proteostatic regulation for treatment of NPC1 disease”
Harrington Discovery Institute (PI, Ory)

Publications

Praggastis M, Tortelli B, Zhang J, Fujiwara H, Sidhu R, Chacko A, Chen Z, Lieberman AP, Davidson C, Walkley SU, Pipalia NH, Maxfield FR, Schaffer JE, and Ory DS. A murine Niemann-Pick C1 (NPC1) I1061T knockin model recapitulates the pathological features of the most prevalent human disease allele. J Neuroscience,  35:8091-8106, (2015).

Ebrahimi-Fakhari D, Wahlster L, Bartz F, Wehrenbeck-Ueding J, Praggastis M, Zhang J, Joggerst-Thomalla B, Theiss S, Grimm D, Ory DS, and Runz H. Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-Pick type C1 disease cells. Hum Mol Genet 25 (16): 3588-3599, (2016).

Chung C, Puthanveetil P, Ory DS, and Lieberman AP. Genetic and pharmacological evidence implicate cathespsin in Niemann-Pick C cerebellar degeneration. Hum Mol Genet  25:1434-46, (2016).

Updated January 2019

Description

Multiple sclerosis (MS) is a highly debilitating disease of the central nervous system that affects millions of people worldwide. In MS patients, immune cells (that normally fight viruses and bacteria) are attacking components of their own body in the central nervous system. This “autoimmune” attack is believed to be mainly orchestrated by white blood cells called lymphocytes, a specific type of immune cells. Lymphocyte auto-reactive responses can be counter-regulated by other immune cells, including some white blood cells called plasmacytoid dendritic cells (PDCs). Our preliminary data show that PDCs exert a protective role in an animal model of MS. The aim of this project is to determine whether and how PDCs in MS patients lose their protective affect. Our studies will indicate if selective manipulation of this cell type could be suitable to ameliorate or cure MS.

Updated January  2019