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Principal Investigator: Subo Yuan
Organization: UNIVERSITY OF TEXAS MED BR GALVESTON
Fiscal Year: 2024
Award: $400,000
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY
Sensory neuropathy (SN) is the most common comorbidity in Human Immunodeficiency Virus-1(HIV-1)
infected-patients (hHIV-SN), which affects 60% of the 37.9 million HIV infected patients in this world. hHIV-SN
is particularly resistant to existing pain relief therapies and now there is no FDA approved HIV specific
analgesic available due to poorly understanding of the hHIV-SN pathogenesis. In order to develop disease-
specific and mechanism-based therapeutics for hHIV-SN, we must fully elucidate the underlying mechanisms.
Healthy skin is mainly innervated by nociceptors labeled by protein gene product 9.5 (PGP9.5+) to generate
nociception and the degeneration of PGP9.5+ nociceptor is a critical pathological mark of hHIV-SN. Growth
associated protein (GAP43) labels the newly sprouted nociceptor (GAP43+). PGP9.5+ and GAP43+ nociceptors
have distinctly neurotrophic dependency on glial cell line-derived neurotrophic factor (GDNF) and nerve growth
factor (NGF) respectively and the expression of GDNF and NGF are regulated by Wnt5a. Wnt5a is a secreted
signaling protein in the Wnt family that plays an important role in axonal remodeling and is also specifically up-
regulated in the spinal cord of HIV-SN patients with chronic pain. Our publication reported that gp120, an
envelope glycoprotein of HIV-1, plays a causative role in neuropathic pain occurred both in gp120-induced
mouse SN (mHIV-SN) and in hHIV-SN patients. The gp120-caused aberrant activation of neuronal Wnt5a in
sensory neuron and in spinal cord are intimately relevant with the development of SN-associated pain in
mouse and in HIV-infected patients as well. Importantly, our preliminary data have shown that Wnt5a-specific
antagonist, Box5, blocks mHIV-SN-associated pain and pathologies. Interestingly, in both of the mHIV-SN and
hHIV-SN, as PGP9.5+ nociceptor degeneration progresses, even close to the point of denervation, chronic pain
remains or worsens, instead of resolving. This phenomenon indicates that the chronic pain in HIV-SN must be
mediated by an alternate novel nociceptor, the sprouted GAP43+ nociceptor which specifically mediates the
HIV-Associated chronic pain. Our central hypothesis is: HIV-1 gp120 causes mHIV-SN by activation of Wnt5a-
NGF mediated sprouting of the GAP43+ nociceptor, which in turn specifically mediates HIV associated chronic
pain. We will test this hypothesis by using mHIV-SN mouse model in three Aims. In Aim #1, we will fully
investigate the interplay of the sprouting of GAP43+ nociceptors and the degenerating of PGP9.5+ nociceptor in
mHIV-SN by using multiple engineering mouse models. In Aim #2, we will determine that gp120-induced the
sprouting of GAP43+ nociceptor is mediated by Wnt5a-NGF pathway by pharmacological and genetic
approaches. In Aim #3, we will determine the therapeutic potential of antagonisms of Wnt5a by its antagonist,
Box5, NGF antagonism by tanezumab and GDNF to treat mHIV-SN in the gp120 mHIV-SN mouse model.
Results from this research will shed light on the essential mechanisms of HIV-SN and illustrate the therapeutic
potential of Wnt5a-NGF-GAP43 sprouting-based approaches for treating HIV-SN.
Terms: <AIDS><AIDS Virus><Ablation><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Acute><Affect><Afferent Neurons><Agonist><Analgesic Agents><Analgesic Drugs><Analgesic Preparation><Analgesics><Anodynes><Antibodies><Antinociceptive Agents><Antinociceptive Drugs><Axon><B-50 Protein><Back><Calcitonin Gene-Related Peptide><Clinical><Closure by Ligation><Complication><Data><Denervation><Dependence><Development><Disease><Disorder><Dorsal Horn Cells><Dorsal Horn Neurons><Dorsal Horn of the Spinal Cord><Dorsal Root Ganglia><Dorsum><Engineering><Exhibits><FDA approved><Family><GAP-43><GAP-43 Protein><GAP43 Protein><GDNF><GDNF gene><Gene Proteins><Generalized Growth><Glycoproteins><Growth><Growth Associated Protein 43><HIV><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV env Protein gp120><HIV-1><HIV-I><HIV1><HTLV-III gp120><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Infection><LAV-HTLV-III><Label><Ligation><Lymphadenopathy-Associated Virus><Measures><Mediating><Mediator><Medulla Spinalis><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Nerve Cells><Nerve Growth Cone Membrane Protein GAP-43><Nerve Growth Factor Pathway><Nerve Growth Factors><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neurocyte><Neurologic Disorders><Neurological Disorders><Neuromodulin><Neuronotrophic Factors><Neurons><Neuropathy><Neurotrophic Proteins><Nociception><Nociceptors><Pain><Painful><Pathogenesis><Pathologic><Pathology><Pathway interactions><Patients><Peripheral><Peripheral Sensory Neuropathy><Phase><Phosphoprotein B-50><Phosphoprotein F1><Phosphoprotein pp46><Physiologic><Physiological><Play><Posterior Horn Cells><Posterior Horn Neurons><Protein Gene Products><Proteins><Publications><Reporter><Reporting><Research><Resistance><Role><Scientific Publication><Sensory Neurons><Severities><Signaling Factor Proto-Oncogene><Signaling Pathway Gene><Signaling Protein><Skin><Spinal Cord><Spinal Cord Contusions><Spinal Cord Trauma><Spinal Ganglia><Spinal Nerves><Spinal Trauma><Spinal cord injured><Spinal cord injury><Spinal cord posterior horn><Spinal nerve structure><Testing><Therapeutic><Tissue Growth><Traumatic Myelopathy><Treatment Efficacy><Up-Regulation><Upregulation><Virus-HIV><afferent nerve><allodynia><antagonism><antagonist><chronic pain><chronic pain patient><co-morbid><co-morbidity><comorbidity><conditional knock-out><conditional knockout><developmental><dorsal root ganglion><effective therapy><effective treatment><experience><genetic approach><genetic strategy><glial cell-line derived neurotrophic factor><gp120><gp120 ENV Glycoprotein><gp120(HIV)><innervation><intervention efficacy><life span><lifespan><mouse model><murine model><nerve supply><neural growth associated protein><neurological disease><neuronal><neuropathic><neuropathic pain><neurotrophic factor><neurotrophin><neutrophin><nociceptive><nociceptive neurons><novel><ontogeny><pain killer><pain medication><pain patient><pain relief><pain reliever><pain-sensing neurons><pain-sensing sensory neurons><pain-sensing somatosensory neurons><painful neuropathy><painkiller><pathway><patient with chronic pain><pharmacologic><planar cell polarity><prevent><preventing><relieve pain><resistant><sensory nerve><sensory neuropathy><social role><therapeutic efficacy><therapeutic evaluation><therapeutic testing><therapy efficacy>