Supplement to Pathogenesis of HIV-associated sensory neuropathy

University Of Texas Med Br Galveston, Galveston TX

Investigators

Linked publications & trials

Abstract

Project Summary HIV-1-associated sensory neuropathy (hHIV-SN) remains prevalent in antiretroviral therapy era, affecting 30-60% of 39.9 million HIV patients worldwide, also with 100% cases diagnosed with autopsy in HIV patients with chronic pain (hHIV-PAIN). We characterized protein gene product immunopositive (PGP9.5+) and growth associated protein immunopositive (GAP43+) nociceptors and investigated the mechanism for GAP43+ nociceptor sprouting in mouse. The parent R01 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-PAIN with three aims: 1. Investigate the interplay of the sprouting of GAP43+ and the degenerating of PGP9.5+ nociceptors. 2. Determine the activation of Wnt5a-NGF pathway mediated the sprouting of GAP43+ nociceptor. 3. Determine the therapeutic potential of antagonisms of Wnt5a, NGF in inhibiting sprouting and GDNF rebuilding healthy skin innervation. Finished works were submitted as year 1, 2, 3 progress reports, two corresponding author preprints and three meeting abstracts, including one sfn abstract. After 3.5 years awarded work, we defined the characteristics of sprouted GAP43+ and relevant mechanisms and studied how to target sprouting in mouse HIV-SN (mHIV-SN). The Proposed administrative supplement work is within the scope of parent R01: To visualize and track the dynamic changes of nociceptors in mHIV-SN, target the NGF to inhibit sprouting GAP43+, rebuid healthy skin innervation with GDNF, the PGP9.5+ dependent neurotrophic factor. Aim 1. To build up in vivo nociceptor visualizing platform and dynamically observe nociceptors changes. Aim 2. To investigate the gp120 induced upregulation of Wnt5a mediates NGF upregulation in spinal cord, DRG neurons and skin that all contribute to the GAP43+ ending sprouting. Aim 3. To examine the antagonism effects of NGF (tanezumab) in treating of mHIV-SN by inhibiting the sprouting of GAP43+ and rebuild healthy skin innervation by GDNF. The proposed work is innovative, because it represents a new and substantive progress in nociceptor research. Successfully finish the proposed work will provide novel concept that nociceptor sprouting is a critical mechanism for chronic HIV-PAIN, that contradicts to long time dominated nociceptor degeneration concept. The reason I apply the administration supplement is that I was diagnosed age-related macular degeneration (AMD) two years ago with decreasing vision. AMD has no FDA approval treatment until November 2024, a new therapy was approved that can significantly improve version. I scheduled a 12-month therapy that will begin two months later. I hope the application with 1.5-year award period, can effectively help me finish the therapy and bring me back to fully loaded work.