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309
Christine Webber
Medicine
Division of Anatomy
Stopping the Pain: Key Role for p75 Receptor Inhibition in
Treatment of HIV-related Chronic Pain
2
1/6/2014
5/30/2014
Yes
Biochemistry, Biological Sciences, Medical Sciences,
Molecular Biology, Neuroscience
No Preference
Key Role for p75 Receptor Inhibition in Treatment of HIVrelated Chronic Pain A. SUMMARY OF PROPOSAL A.1
Clinical Background: Infection with Human
Immunodeficiency Virus (HIV) causes chronic Distal
Sensory Polyneuropathy (DSP) in more than 50% of
patients often leading to depression and severe cases,
suicide. Although antiretroviral HIV therapies stop its
progression, they can exacerbate the debilitating pain and
paresthesia that comprising the major symptoms of HIVDSP. These symptoms originate from dysfunction and
axonal retraction in sensory dorsal root ganglion neurons
(DRGN), but underlying cellular mechanisms are
unknown. As conventional analgesics fail to treat the
symptoms of HIV-DSP, molecular pathways need to be
identified for developing novel drug targets to alleviate
symptoms and prevent the progression of this chronic pain
syndrome. A.2 Specific Background and Aims of this
Proposal: Viral protein R (Vpr) is produced by HIV-infected
macrophages and our laboratories have recently made
important discoveries related to its role in DSP, its direct
effect on DRGNs, and potential therapies to block its
effects: 1) Our in vivo studies revealed that chronic
exposure of Vpr in our HIV-mouse model led to somatic
sensory nerve denervation and footpad DSP60. Results
from in vitro studies illustrated that recombinant Vpr (i)
increased axon excitability, (ii) raised intracellular calcium
levels, (iii) altered signalling pathways, and (iv) hindered
axon outgrowth of DRGN. In short, Vpr negatively impacts
DRGN in vivo and in vitro. 2) Antagonism of the p75
receptor with the functional antibody, REX, protected
DRGN from all above Vpr-induced effects in vitro. Our
primary goal in this study is to determine if p75 receptor
antagonism within our HIV mouse model protects footpad
denervation and prevents DSP. Aim 1: Determine if p75
pathway antagonist, LM11A-31* acts in a similar manner
to REX to block the effects of Vpr in DRG sensory
Other Notes:
neurons in vitro. Aim 2: Determine the electrophysiological
imaging (nerve conduction, calcium imaging) of DRGN in
the presence of Vpr +/- LM311A Aim 3: Orally treat our
HIV-mouse model with LM11A-31 to establish if this
treatment rescues our HIV mouse model from Vpr-induced
epidermal denervation and mechanical allodynia. *LM11A31 is an engineered small molecule p75 antagonist
shown, through oral gavage of different transgenic mice,
to effectively and safely block the p75 pathway in vivo. We
are in collaboration with engineer and proprietor, Dr. Frank
Longo at UCSF who is currently applying for its Phase I
clinical trial to test its safety in patients. A.3 Anticipated
Outcome: We anticipate that LM11A-31 will protect our
HIV mouse model from epidermal denervation and DSP
and thus lay the essential pre-clinical groundwork for a
Phase 2 clinical trial to investigate whether LM11A-31 is a
curative treatment for HIV-induced DSP. A.4 Significance:
If our hypothesis is correct, LM11A-31 may provide the
cure for neuropathic pain and paresthesia in HIV patients.
If not, the research will likely lead to alternative promising
routes for treatment by elucidating the mechanisms
involved in the responses of DRGN to Vpr. Finally,
Diabetic-DSP has similar epidermal denervation and
mechanical allodynia as HIV-DSP; thus it is possible that a
successful therapy for HIV-DSP will also be an effective
treatment for Diabetic patients suffering from DSP.
I am a flexible supervisor and encourage student input
and feedback. There are several experiments to choose
from to contribute to this project.