Neurosurgery Research

Neurosurgery Research Projects

Laboratory of Naomi L. Sayre, Ph.D.
Our laboratory is interested in the processes that affect repair and recovery after brain damage, with particular emphasis on the role that cholesterol homeostasis plays in these processes. Our research focuses on two cell types in particular-astrocytes and neural stem cells. As the primary supportive cells in the brain, astrocytes also regulate cholesterol homeostasis, and so have unique potential to affect recovery after brain damage due to trauma or stroke. Neural stem cells travel to the site of brain injury, where they play a role in recovery that has not been fully elucidated. Our laboratory approaches include neurosurgical mouse models of traumatic brain injury, traumatic spine injury, and middle cerebral artery occlusion. We similarly utilize state of the art in vivo optical imaging, biochemical, histological, and cell-culture based approaches as research tools.

 


 

Confocal image of astrocytes immunolabeled for LRP1 (red). Nuclei of individual cells are stained with DAPI (blue).
Confocal image of astrocytes immunolabeled for LRP1 (red). Nuclei of individual cells are stained with DAPI (blue).
Low-density lipoprotein receptor related protein 1 (LRP1)
LRP1 is an important plasma membrane receptor involved in the receptor mediated endocytosis of lipoproteins from cerebrospinal fluid. In addition, LRP1 binds to a range of molecules and proteins, both from the extracellular space and on the plasma membrane, thereby regulating their amount in either compartment. Such proteins include Apolipoprotein E, amyloid beta, tumor necrosis factor receptor, bone morphogenic protein signaling mediators, and multiple others. Altogether, we hypothesize that by modulating plasma membrane protein expression, LRP1 has the potential to significantly influence cellular response after brain damage. To this end, we utilize genetic mouse models to study the effect of LRP1 knockout specifically within astrocytes or neural stem cells, and the effect that cell-specific knockout might have on the brain response after damage.

 


 

Confocal image of astrocytes immunolabeled for LRP1 (red). Nuclei of individual cells are stained with DAPI (blue).
Proposed model of function blocking antibody.
Cx43 is normally localized into gap junctions between cells or as hemichannels on the plasma membrane.
A) Pathological opening of Cx43 hemichannels result in propagation of secondary injury, activation of astro/microglia, and inflammation.
B) We propose that preventing pathological opening of Cx43 hemichannels prevents release of molecules, enabling astrocytes to act as caretaker cells and prevent spread of secondary injury.
Connexin-43 function blocking antibodies for the treatment of spinal cord injury
In collaboration with Dr. Jean Jiang in the Department of Biochemistry, we are testing the effect of a function blocking antibody to Connexin-43 (Cx-43) hemichannels on damage after spinal cord injury. Our long-term goal is to improve the therapeutic potential of patients who suffer from traumatic spinal cord injury (SCI). Every year, thousands of patients are admitted to U.S. hospitals due to traumatic spinal injury. Part of the post-injury neuroinflammatory process is the activation of astrocytes and formation of a glial scar resulting in an impermeable milieu for axonal regeneration. At the time of injury, astrocytic Cx43 hemichannels open, releasing a quantity of ATP, glutamate, ions and other molecules. The net result of pathological opening of the Cx43 hemichannels is an increase in metabolic stress, imbalanced ion homeostasis, excitotoxicty, and inflammation at the site of injury. Altogether this causes spread of secondary damage after the initial injury. We hypothesize that inhibiting the function of Cx43 hemichannels after SCI will limit the size of spinal cord lesion after trauma and improves functional recovery. Recently, Dr. Jiang’s laboratory developed a potent antibody that blocks Cx43 hemichannels. Dr. Sayre’s laboratory developed a mouse model of SCI, which we are using to test the effect of Cx43 inhibition on SCI damage. We ultimately aim to utilize this antibody as an approved treatment for SCI.

 


 

Selected publications:
Stimulation of astrocyte fatty acid oxidation by thyroid hormone is protective against ischemic stroke-induced damage.
Sayre NL, Sifuentes M, Holstein D, Cheng SY, Zhu X, Lechleiter JD.

Purinergic receptor stimulation decreases ischemic brain damage by energizing astrocyte mitochondria.
Sayre NL1, Chen Y, Sifuentes M, Stoveken B, Lechleiter JD.

The trifunctional protein mediates thyroid hormone receptor-dependent stimulation of mitochondria metabolism.
Chocron ES*, Sayre NL*, Holstein D, Saelim N, Ibdah JA, Dong LQ, Zhu X, Cheng SY, Lechleiter JD.

Recovery from liver disease in a Niemann-Pick type C mouse model.
Sayre NL1, Rimkunas VM, Graham MJ, Crooke RM, Liscum L.