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FACIAL PAIN RESEARCH FOUNDATION

 

Current Projects, April, 2017

 

 

 

Submitted by:

 

Douglas K. Anderson, Ph.D.

 

Eminent Scholar Professor and Chair Emeritus

 

Department of Neuroscience

 

University of Florida College of Medicine

 

And

 

Director of Research and Trustee

 

Facial Pain Research Foundation  

 

“Answering a far-out seemingly abstract question can turn out 

 to be a very smart thing to do”. 

                                     Herman Wouk

  Trigeminal Neuralgia (TN), which is considered to be is one of the most painful afflictions known

to humans and is one example of neuropathic pain which is pain caused by injury to or malfunctioning

of the nervous system. 

Despite the debilitating effects chronic pain has on the activities of daily living of individuals with painful conditions like TN and on the cost these afflictions add to our health care system (greater than $100 billion/year), research funding from federal agencies, primarily the National Institutes of Health (NIH)

and pharmaceutical companies continues to be insufficient.  This inadequacy of funding from traditional

sources has led the growing realization that discovering the root cause of and treatment for

TN and other neuropathic pain conditions is going to have to be accomplished with funding from

the private sector.  To this end, The Facial Pain Research Foundation (FPRF) was created in

January, 2011 to provide the critical elements that are necessary and sufficient to study

these facial pain conditions

.

Consequently, the sole mission of the FPRF is “…to establish a well-funded translational

(i.e., fundamental discovery to clinical application) research continuum that is dedicated to identifying

the mechanisms underlying neuropathic facial pain and to develop novel new therapeutic strategies

that will permanently stop the pain of TN and related neuropathic pain syndromes”.

 

  Since its inception a little over six years ago,the FPRF has raised $3,345,021 to support

five separate and distinct research projects.  The FPRF used three fundamental criteria

in choosing which proposals would be considered for funding:  (1) the projects

were novel and unique; (2) the investigator(s) responsible for each project are among the leading

researchers in their respective fields; and (3) all of the projects were not “cut from the same cloth”,

i.e., there was significant diversification in the research strategies among the projects. 

It is important to note that these FPRF funds have also served in a multiplier capacity in that

some of our investigators have used FPRF support as seed funding to generate the necessary

preliminary data which contributed to these investigators acquiring large grants from the NIH.

The purpose of this yearly update is to briefly summarize these five projects and to highlight

the progress that each achieved in 2016. 

  

 

Investigating Protein-Lipid Interactions in Peripheral Nerve Myelin 

 

Lucia Notterpek, Ph.D. (Principal Investigator) 

Professor and Chair 

Department of Neuroscience 

University of Florida College of Medicine 

 

Project 1: Cholesterol homeostasis in peripheral nerve myelin 

 

During the past year, Dr. Notterpek and her research team have made excellent progress

on their cholesterol homeostasis project.  As a result, various team members have given

presentations on their findings at several national meetings.  Dr. Notterpek continues her

investigation of the proteins and lipids that make up peripheral nerve myelin. 

For these studies, she used (and continues to use) a genetic animal model that allows

for the examination of compression induced peripheral neuropathies. 

This model was created by deleting the peripheral myelin protein 22 (PMP22) gene

which causes abnormalities in the myelin membrane, that makes it predisposed

to compression-induced degeneration.  Dr. Notterpek found that a normal

functioning PMP22 is responsible for forming specific microdomains (clusters of lipids and

proteins in membranes called lipid rafts) in the Schwann cell membrane, that are critical for

myelin stability. These microdomains are enriched in cholesterol and the membrane localization

appears to depend on the correct expression of PMP22.  To corroborate these findings, they

  have inserted mutated amino acids in the PMP22 protein that have been predicted to be critical for cholesterol binding and are now in the midst of examining the properties and functionability of

these mutated amino acid carrying PMP22 proteins in living cells. During their study of the

PMP22-deficient mice, they detected systemic alterations in lipid metabolism in neuropathic

animals which were associated with pathology in the liver.  Further study produced preliminary

data which suggested that this liver pathology caused an inflammatory response that could

amplify the nerve pathology through circulating macrophages. To test if the liver and

neuro-pathologies were linked, for six weeks they fed rats a diet high in “bad fats” that is known

to induce cardiovascular disease in rodents. Exposure of the animals to this high fat diet

indeed led to circulatory lipid abnormalities, and enhanced liver pathology, including

inflammation. As expected, this bad high fat diet also enhanced the neuropathology,

including motor and myelin defects. With these intriguing preliminary results as a foundation,

this past February, Dr. Notterpek submitted a large NIH grant proposal titled Dysregulated lipid metabolism, a disease modifier in PMP22-dependent neuropathies”. The overall goal

of this project is to (a) provide data to gain a better understanding of the heterogeneity

in clinical presentation among hereditary neuropathic patients and (b) recognize the vulnerability

of certain individual to compression induced neuropathies, such as in trigeminal neuralgia. 

They hypothesize that dyslipidemia is a disease- modifying comorbidity in neuropathic patients.

 

Current efforts are focused on assembling these results into a major manuscript, which will

include some of the molecular mechanisms underlying the observed pathologies. The unexpected dysregulation of hepatic cholesterol metabolism with the induction of fatty liver and enhanced

inflammation in neuropathic animals has opened a new field for future studies for Dr. Notterpek

and her team which has clear translational significance.  They also have a second manuscript

planned, which will use molecular and cellular approaches in combination with electrophysiology

to dissect how changes in lipids, particularly cholesterol, affect the biological properties of myelin. 

 

Presentations in poster format:

  

SFN 2016 

 

Ye Zhou, Sooyeon Lee, Alex I. Fethiere, Hagai Tavori, Sergio Fazio, Angela Corona, Gary E. Landreth,

Lucia Notterpek. Altered cholesterol trafficking in mice deficient in peripheral myelin protein 22 

 

 

ASN 2017

 

  

Ye Zhou, Alex I. Fethiere, Elliott Soto, Lucia Notterpek. Cholesterol homeostasis in

neuropathic Schwann cells International Peripheral Nerve meeting July 2017

 

 

 

International Peripheral Nerve Meeting July, 2017

 

Zhou Y, Tavori H, Lee S, Al Salihi M, Fazio S, Notterpek L. Dysregulated lipid

metabolism in the absence of peripheral myelin protein 22 (pmp22).

 

Project 2: Cholesterol homeostasis in peripheral nerve myelin,

with a focus on statins

 Myelin is an insulating sheath around nerves that promotes the electrical conduction of signals.

 It is composed of certain proteins and lipids, principally cholesterol, which helps stabilize the

membrane.  Most individuals diagnosed with the facial pain condition termed trigeminal neuralgia,

have a localized region on their trigeminal nerve with evidence of varying degrees of demyelination.

  Although the cause(s) for having this localized myelin damage is not known, the close proximity

of the Superior Cerebellar Artery (with its strong pulsations) to the trigeminal nerve could be the

trigger for or a substantial contributor to the evolution of this lesion with the subsequent development

of debilitating pain in susceptible individuals.  In addition, this demyelinating lesion could involve

the use of cholesterol reducing drugs, such as statins.  A survey conducted by the Instructional

Management Systems (IMS) found that there are nearly 15 million Americans are currently taking

a statin medication who after two years of continued use showed evidence suggesting that

neuropathies could occur.  Moreover, continued use of a statin increased the risk of developing

Type 2 diabetes2. With serious side effects surrounding the use of statins, it is of great

importance to understand the pathophysiology of this medication and its influence

on myelin damage and diabetes. 

 

Dr. Notterpek hypothesizes that in certain individuals, statins alter the stability of myelin making

it prone to localized compression-induced demyelination. If correct, this linkage could explain

the increasing rise of trigeminal neuropathy and other neuropathies in patients taking

cholesterol-lowering medication. Statins inhibit the cholesterol-synthesizing enzyme,

HMG-CoA reductase, which reduces the level of cholesterol synthesized by the liver. I

t can also cross the blood-brain barrier and is capable of inhibiting remyelination by blocking

glial progenitor differentiation3---a reversible side effect once the subjects discontinue the use of statins. 

 

To test their hypothesis of a statin-induced weakening of peripheral nerve myelin, they propose

to use their laboratory tool kit to experimentally manipulate (elevate or reduce) the levels of cholesterol

in glial cells from mice that are prone to the development of compression induced demyelinating

neuropathy.  In collaboration with neurologists, Dr. Notterpek proposes to nudge this project

towards clinical application starting with this first step of performing a retrospective clinical data

analysis to see if tghey can find any evidence of a link between the lipid and cholestero

l profile of an individual and the development of trigeminal neuralgia or other

demyelinating diseases.

 

The postdoc (Dr. Al Salihi) for this project started work on this project January 1, 2017 and

is making good progress in learning the literature and experimental techniques. 

 

References:

 

1.     The Link between Nerve Damage and Statin Drugs. (n.d.). Retrieved March 02, 2016, from http://articles.mercola.com/sites/articles/archive/2012/01/25/nerve-damage-with-cholesterol- meds.aspx

 

2.     Hitman, G. A. (2014). Statins and diabetes. Diabet. Med. Diabetic Medicine, 31(6), 639-639. Retrieved March 2, 2016, from http://www.ncbi.nlm.nih.gov/pubmed/26892999

 

3.     Miron, V. E., Zehntner, S. P., Kuhlmann, T., Ludwin, S. K., Owens, T., Kennedy, T. E., Antel, J. P. (2009). Statin Therapy Inhibits Remyelination in the Central Nervous System.

      The American Journal of Pathology, 174(5), 1880-1890.

      Retrieved from http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2671276/

 

 

 

“Mapping Towards a Cure: Identification of Neurophysiologic

Signatures of Trigeminal Neuralgia Pain.”  

John K. Neubert, D.D.S., Ph.D., University of Florida (Project coordinator, animal modeling) 

Mingzhou Ding, Ph.D., University of Florida (Human imaging) 

Marcelo Febo, Ph.D., University of Florida (Animal imaging)

Robert M. Caudle, Ph.D., University of Florida (Therapeutics)

Todd Golde, M.D., Ph.D. at the University of Florida

 

Andrew H. Ahn, M.D., Ph.D., Eli Lilly Company, IN (Consultant)

 

John K, Neubert, D.D.S., Ph.D. continues to lead an impressive team of co-investigators

(Mingzhou Ding, Ph.D., Robert Caudle, Ph.D., Marcelo Febo, Ph.D., Todd Golde, M.D., Ph.D.

at the University of Florida (UF) and Evelyn F. and William L. McKnight Brain Institute (MBI)

of the University of Florida. This talented group represents experts in the areas of orofacial pain,

functional imaging, pharmacology, and viral vector therapeutics that is focused on identifying the neurophysiological signature of TN pain and provide promising new therapies. 

 

This is a complex, translational project whose purpose is to determine if the neurobiology of TN in rats replicates or is very similar to the neurobiology of TN in humans.  Using state of the art magnetic

resonance (MR) scanners, the UF team is attempting to identify and compare in both TN patients

and rats, the individual imaging patterns caused by the pain induced activation of different areas

in the brain and spinal cord. The specific areas of the brain and spinal cord that “light up” or are

activated by TN pain are called “signature” centers of activity. These signature centers will be

the targets for treatments with any new therapies their team has identified and/or developed. 

In 2016, Dr. Neubert’s team made significant progress towards completing the Phase One

Objectives of this project as described below. 

  

 

 

 

 

 

 

Human Studies.

 

The recruitment goal for the human imaging study was originally 25-30 subjects. To date, Dr. Neubert’s group has recruiting 16 subjects with 11 new subjects scanned last year (6 were diagnosed with TN1, 2 with TN2, and 3 with TN1/TN2). 

  Working in a world-class environment at UF and the MBI allows the investigators to benefit from advances in techniques that were not available at the conception of the study. The Ding laboratory is now able to study free-water content in the brain of TN subjects to provide a potential biomarker for neuroinflammation.  

Dr. Neubert’s team has discovered promising regions of pain induced brain activation that warrant further investigation. In particular, a region of the brain (insula) involved as a gateway/relay station for pain processing in the brain show differences in free water content between TN subjects that

had surgery as compared to those without surgery (Figs 1, 2).  Collectively, these findings are

important because they may provide insight into better diagnosing TN as well as providing new

areas for the application of novel therapies. While preliminary, these results were sufficiently

encouraging for them to increase their recruitment by additional 30-40 TN subjects. The FPRF

and UF MBI have generously provided the additional funds needed to image these subjects

in hopes of reaching their target in 2018. 

 

 

 

 

 

Animal studies

 

 

 

Dr. Febo’s group has completed approximately 50 high-resolution fMRI scans of rats with

various orofacial pain conditions and treated them with different therapeutic agents. Data

presented in Figure 3A shows that nerve injury (CCI) significantly increased connectivity

in the ventral tegmental area (VTA) as compared with rats receiving just a sham (control)

procedure. This finding could cause Dr. Febo to focus on the VTA as a target for treatments.

Note that the data generated by this study is both voluminous and complex and, thus, is

very time consuming to analyze and interpret. Dr. Febo’s group is in the midst of processing

this large data set.  

In a pilot study with Dr. Golde’s group, Dr. Neubert’s team has injected virus-vectors

that can either turn-on or turn-off the pain system. Fig. 4 demonstrates that treatment

with a substance called AAV-DREADDs to the trigeminal nerve can significantly increase

orofacial pain. This is important because this is a critical step for developing a reliable

orofacial pain model.

 As with the first year of this project  Dr. Neubert’s team continues to have issues regarding

subject enrollment and staffing difficulties. To help increase enrollment, the FPRF has sent

out emails to thousands of potential subjects. Additionally, they have agreed to help provide

need-based travel funds for subjects to come to Gainesville, FL to participate

 in the study.

 

  

   

Plans for year 3:                            

 Recruit more subjects to scan – plan to expand recruitment with travel support

  • Study 50-100 animals using different trigeminal injury models

    • Evaluate compounds from Dr. Golde’s and Dr. Caudle’s laboratories

      for pain relief and image the brains of these animals using MRI

    • Establish the ability to do EEG & MRI studies in these animals

 

           

“Cell Replacement Therapy as a Treatment for

 

 

Injury-Induced Neuropathic Pain”

 

 

Allan Basbaum, Ph.D., FRS

Professor and Chair

Department of Anatomy

University of California San Francisco 

 

As described in a previous report, Dr. Basbaum’s laboratory has developed a powerful

new approach to reversing the abnormal hyperexcitability that underlies many neuropathic

pain conditions including trigeminal neuralgia. Although there are many explanations for the

hyperexcitability that occurs after nerve injury, Dr. Basbaum’s laboratory has focused on the

loss of inhibitory controls interposed between the peripheral nerve fiber input and the

central nervous system circuits that transmit that input to the brain where pain is perceived.

There is now considerable evidence that the loss of inhibitory control results from a

significantly reduced function of a population of nerve cells that synthesize the inhibitory

neurotransmitter, GABA. With these findings confirmed, Dr. Basbaum’s group took on the

task of developing a strategy for rebuilding those lost or dysfunctional circuits. They chose

a transplant paradigm and, to date, have documented the survivability and functionality of

precursors of GABA nerve cells that have been transplanted into the spinal cord of a

mouse model of neuropathic pain created with a hindlimb peripheral nerve injury. Results

reported in a series of publications from Dr. Basbaum’s laboratory established that these

nerve cells integrate incredibly well into host spinal cord circuits and restore inhibition, the

result of which is a near complete loss of the hyperexcitability of spinal cord neurons and

most importantly of the mechanical hypersensitivity that occurs in this neuropathic pain model.

 

 Building upon these studies, Dr. Basbaum and his team have now turned their attention

to a model of trigeminal neuropathic pain. In this model, there is a partial nerve injury of

a major branch of the trigeminal nerve, namely the infraorbital nerve. Within days of the

injury, the mouse develops hypersensitivity of the face region innervated by the infraorbital

nerve. It is of particular interest that the test of hypersensitivity involves a very powerful

behavioral model recently developed by John Neubert, D.D.S., Ph.D. of the University of Florida

who is another grantee of the FPRF. Following upon the methods used to treat hypersensitivity

of the spinal cord after hindlimb peripheral nerve injury, Dr. Basbaum’s team of investigators

transplanted GABA precursor cells into the trigeminal nucleus caudalis, which is the brainstem

nucleus that receives input from the infraorbital nerve. The behavior of the mice was followed

for weeks after the transplant and   once again the transplants reversed the mechanical

hypersensitivity created by this model. To what extent damage to the infraorbital nerve models

human trigeminal neuralgia remains to be determined. Nevertheless, it is significant that

Dr. Basbaum’s group has shown that these GABA precursor cell transplants can also reduce

both the mechanical and thermal hypersensitivity that occurs after chemotherapy treatment.

Thus, a very important finding arising from Dr. Basbaum’s experiments is that his findings are

consistent with there being a common etiology underlying nerve injury-induced

neuropathic pain conditions.

 

 In ongoing studies, Dr. Basbaum’s laboratory, in collaboration with scientists at Neurona,

are evaluating the utility of transplanting human embryonic stem cells that have been modified

to take on properties of GABAergic nerve cells. Those studies are critical first steps in the

development of an approach to treatment clinical pain conditions. Hopefully, Dr. Basbaum’s

next report will bring encouraging news on that front.

 

 

 

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Success in answering critical questions about the role of genes in TN and other

nerve-related facial pains relies on private support. Here are ways in which donors

at all levels can join The Facial Pain Research Foundation in finding a solution:

  • Support full expenses of one patient      in the study:     $1,770
  • Pay for the genotyping of one research      participant:    1,100
  • Help with the phenotyping costs for      one participant:     600
  • DNA extraction from one person’s      saliva samples           40
  • Pay for saliva kit & shipping cost      for one participant      30
 

 

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