Pharmaceutical Sciences; Blanchette Rockefeller Neurosciences Institute
Ph.D. in Pharmacology & Toxicology, Florida A&M University, School of Pharmacy,
Blood-Brain Barrier Research Group, Department of Medical Pharmacology, University
of Arizona, Tucson, AZ
Dr. Huber's lab will be seeking 1 - 2 new graduate students for the Fall 2016 semester.
If you are interested in joining his lab, please contact Dr. Huber directly.
Under normal physiological conditions, the blood-brain barrier (BBB) is a physical
and metabolic partition between the systemic circulation and the microenvironment
of the brain, which serves to establish and maintain a highly regulated environment
necessary for optimal neuronal function. The BBB is situated at the level of the
cerebral microvasculature and is characterized by a lack of pinocytotic activity
and the presence of "epithelial-like" tight junctions that allow the endothelium
to closely regulate the passage of solutes into and out of the brain. In addition,
the BBB has a number of channels and transporters that regulate the passage of
nutrients into and wastes and toxins out of the brain. However, these same attributes
that are necessary for proper neuronal function create a formidable obstacle for
the entry of pharmaceutical agents into the brain; therefore, many CNS-associated
pathologies (neurodegenerative diseases, multiple sclerosis, and stroke) are under-treated
or not treated at all. My research focuses on two facets of BBB research: improving
drug delivery to the CNS and characterizing the functional and structural integrity
of the BBB in health and disease.
Effect of age on BBB alterations following MCAO and reperfusion
Age is a paramount risk factor for ischemic stroke. The impact of age and its relationship
to the development of ischemic injury is an understudied, yet critical, area for
investigation that serves the missions of NINDS and NIA by gaining a better understanding
of stroke pathophysiology and the opportunity for improved therapeutics. The long
term goal for this proposal is to improve the outcome of patients whom have suffered
a stroke. As a necessary first step, we will obtain a functional and structural
characterization of the blood-brain barrier (BBB) following an ischemic episode
in aged rats as a means to assessing and developing therapeutic options that can
be effective for people as well as laboratory animals. The rationale for the proposed
research is that current animal stroke models do not adequately address age-related
changes in the BBB; thus, hindering the ability to translate promising stroke therapies
from the lab to the clinic. The objective of this application is to determine the
impact age has on functional and structural changes occurring at the BBB following
middle cerebral artery occlusion (MCAO) and reperfusion with tissue plasminogen
activator (tPA). Our central hypothesis states that age is a significant risk factor
in ischemic stroke that leads to increased perturbations in BBB function, characterized
by increased permeability and alterations in endothelial cell-cell contacts. We
propose three specific aims to test our hypothesis: 1. Investigate relative size
and regional localization of blood-brain barrier functional changes following MCAO
and tPA reperfusion in aged rats using in situ brain perfusion and confocal microscopy.
2. Identify BBB tight junction regulatory proteins [occludin and zonula occludens-1
(ZO-1)] following MCAO and tPA reperfusion using electrophorectic techniques and
confocal microscopy. 3. Evaluate the effect of pharmacological modulation of BBB
during MCAO and tPA reperfusion in aged rats using in situ brain perfusion. We
expect that these findings will clearly show that age has profound effects on BBB
function and structure that must be taken into account when developing and screening
therapeutics to reduce stroke morbidity and mortality. Stroke is a disease of the
elderly. Using an animal stroke model that takes age i nto account will have an
impact in our gaining a better understanding how stroke affects the brain and provide
a clinically relevant model for assessing potential neuroprotectants.
Effects of diabetes on blood-brain barrier function and structure
Endothelial cell dysfunction associated with microangiopathy is a primary factor
in the development and progression of diabetes mellitus (DM)-related disabilities,
including blindness, kidney failure, and peripheral neuropathy. While much is known
about DM-induced microvascular alterations of the kidney and retina, the role DM
plays in cerebral microvascular pathogenesis is understudied. Recent clinical evidence
suggests DM-induced changes in the blood-brain barrier (BBB) lead to increased
incidences of vascular dementia, ventricular hypertrophy, lacunar infarcts, hemorrhage,
and may be a predisposing factor for Alzheimer's disease. Our long term goal is
to obtain a functional and structural characterization of the cerebral microvasculature
during DM, in order to provide insight into better, safer approaches to improving
the clinical outcome of DM. The objective of this application is to determine the
impact DM has on the functional and structural changes occurring at the BBB during
DM. The rationale for this study is that
complications of DM are associated with alterations in microvascular function;
however, the BBB remains largely unstudied. Preliminary data suggest that BBB function
and structure are altered during DM and characterized by increased BBB permeability,
regions of greater susceptibility, and alterations in the interactions of the tight
junction regulatory proteins occludin and zonulae occludens-1 (ZO-1). Our central
hypothesis states that DM leads to progressive deterioration of BBB integrity,
characterized by increased permeability and alterations in endothelial cell-cell
contacts. We plan to test our central hypothesis and accomplish the objective of
this application by pursuing the following two specific aims: Specific Aim 1: Investigate
relative size and regional localization of BBB paracellular changes during DM.
The working hypothesis is that DM induces a progressive deterioration in BBB function,
characterized by increased paracellular permeability and a greater number of brain
areas affected as compared to age-matched controls. Specific Aim 2: Identify changes
in tight junction regulatory proteins (ZO-1 and occludin) during DM. The working
hypothesis is that DM induces an increased deterioration of BBB cell-cell contacts,
characterized by changes in ZO-1 and/or occludin expression and localization as
compared to age-matched controls. The proposed work is innovative because it addresses
the significance of BBB functional and structural deterioration during the onset
and progression of DM. It is our expectation that the results of this application
will clearly show that DM has profound effects on BBB function and structure that
must be taken into account when assessing the pathophysiology of long term DM-induced
complications. These results will be significant because they will serve as the
foundation for a programmatic effort to better assess CNS complications in diabetic
patients and serve as the basis for future NIH funding. Major complications associated
with DM are manifest in damage to the vascular system, leading to decreased quality
of life for those who suffer from the disease. Due to the progressive nature of
DM and the unique characteristics of the BBB, effects of DM on the cerebromicrovasculature
are, in many ways, different from other microvascular beds and barrier systems,
such as seen at the retina and peripheral nerves. Often the adverse effects seen
at the BBB can be more insidious as vascular dysregulation is less perceptible
at first and by the time clinical signs are noticeable, neurological damage has
occurred. Understanding how DM progressively alters BBB function and structure
is an under investigated yet important area of DM-related research. We expect this
proposal is a start toward addressing this need and our lab is uniquely qualified
to carry out this research.
Pharmacy & Pharmaceutical Sciences Graduate Student
Neuroscience Graduate Student
- Turner RC, Lucke-Wold BP, Logsdon AF, Robson MJ, Lee JM, Bailes JE, Dashnaw ML,
Huber JD, Petraglia AL, Rosen CL.
Modeling Chronic Traumatic Encephalopathy: The Way Forward for Future Discovery.
Front Neurol (2015); 6:223. doi: 10.3389/fneur.2015.00223. eCollection
2015. Review. PMID: 26579067
- Turner RC, Lucke-Wold BP, Logsdon AF, Robson MJ, Dashnaw ML, Huang JH, Smith
Huber JD, Rosen CL, Petraglia AL.
The Quest to Model Chronic Traumatic Encephalopathy: A Multiple Model and Injury
Front Neurol (2015); 6:222. doi: 10.3389/fneur.2015.00222. eCollection
2015. PMID: 26539159
- Lucke-Wold BP, Nguyen L, Turner RC, Logsdon AF, Chen YW, Smith KE,
Huber JD, Matsumoto R, Rosen CL, Tucker ES, Richter E.
Traumatic brain injury and epilepsy: Underlying mechanisms leading to seizure.
Seizure (2015); 33:13-23. doi: 10.1016/j.seizure.2015.10.002. Epub 2015
Oct 29. Review. PMID: 26519659
- Lucke-Wold BP, Naser ZJ, Logsdon AF, Turner RC, Smith KE, Robson MJ, Bailes JE,
Lee JM, Rosen CL,
Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated
stress reduces cell death after blast-induced traumatic brain injury.
Transl Res (2015); 166(6):509-528.e1. doi: 10.1016/j.trsl.2015.08.005.
Epub 2015 Sep 8. PMID: 26414010
- Lucke-Wold BP, Turner RC, Logsdon AF, Nguyen L, Bailes JE, Lee JM, Robson MJ,
Huber JD, Rosen CL.
Endoplasmic reticulum stress implicated in chronic traumatic encephalopathy.
J Neurosurg (2015); 18:1-16. PMID: 26381255
- Tan Z, Lucke-Wold BP, Logsdon AF, Turner RC, Tan C, Li X, Hongpaison J, Alkon
DL, Simpkins JW, Rosen CL,
Bryostatin extends tPA time window to 6 h following middle cerebral artery
occlusion in aged female rats.
Eur J Pharmacol (2015); 764:404-12. doi: 10.1016/j.ejphar.2015.07.035.
- Logsdon AF, Lucke-Wold BP, Turner RC,
Huber JD, Rosen CL, Simpkins JW.
Role of Microvascular Disruption in Brain Damage from Traumatic Brain Injury.
Compr Physiol (2015); 5(3):1147-60. doi: 10.1002/cphy.c140057. PMID: 26140712
- Lucke-Wold BP, Smith KE, Nguyen L, Turner RC, Logsdon AF, Jackson GJ,
Huber JD, Rosen CL, Miller DB.
Sleep disruption and the sequelae associated with traumatic brain injury.
Neurosci Biobehav Rev (2015); 55:68-77. doi: 10.1016/j.neubiorev.2015.04.010.
Review. PMID: 25956251
- Logsdon AF, Turner RC, Lucke-Wold BP, Robson MJ, Naser ZJ, Smith KE, Matsumoto
Huber JD, Rosen CL.
Altering endoplasmic reticulum stress in a model of blast-induced traumatic
brain injury controls cellular fate and ameliorates neuropsychiatric symptoms.
Front Cell Neurosci (2014); 8:421. doi: 10.3389/fncel.2014.00421. eCollection
2014. PMID: 25540611
- Lucke-Wold BP, Logsdon AF, Turner RC, Rosen CL,
Aging, the metabolic syndrome, and ischemic stroke: redefining the approach
for studying the blood-brain barrier in a complex neurological disease.
Adv Pharmacol (2014); 71:411-49. doi: 10.1016/bs.apha.2014.07.001. Review.
More publications: http://www.ncbi.nlm.nih.gov/pubmed/?term=huber+jd