HIV-1-associated neurocognitive disorders (HAND) remain a significant societal burden in the era of post-antiretroviral therapy. In the brain, regulation of matrix metalloproteinases (MMPs), via their tissue inhibitors (TIMPs), remains an important homeostatic function of astrocytes. Over the past few years of funding we demonstrated that astrocyte-TIMP-1, the multifunctional inducible member of the TIMP family plays key roles in neuroinflammation and HAND neuropathogenesis. We identified critical signaling pathways in regulation of TIMP-1 production by astrocytes and described novel TIMP-1 neuroprotective effects through activation of neuronal pro-survival mechanisms. As a developmental component, we tested multiple nanoformulations and standardized A5P50 as a successful candidate for brain delivery studies. In this competing renewal, we propose to extend our works in novel directions for advancing basic insights into the mechanisms with clinical relevance. Specifically, in this proposal, we will test our overarching hypothesis that astrocyte-TIMP-1 is regulated by upstream promoter elements via C/EBP?-MAPK/p38 signaling (Aim 1) and mediates neuroprotection via a TIMP-1/tetraspanin/integrin tripartite complex (Aim 2). Investigations will include promoter-reporter and overexpression constructs along with the knockdown or inhibition of key signaling elements to decipher these mechanisms. Furthermore, we previously optimized nanoformulations that will be used for successful GFAP-restrictive gene delivery to the brain.
In Aim 3 we propose to test the A5P50 nanoformulations of GFAP-driven astrocyte TIMP-1 expression in the setting of HAND. The GFAP/Tat-transgenic animal model will be used and A5P50-conjugated GFAP driven-TIMP-1 will be administered via tail-vein injection. Changes will be evaluated at the tissue level by analysis of RNA, protein and histopathology for reversal of neural damage and deleterious side effects on extracellular matrix. Behavior studies will be performed for proof-of-concept of clinical outcomes. Combined molecular, cellular, in vitro, in vivo and translational approaches will be employed. Taken together, studies proposed in this renewal will not only unravel novel mechanisms underlying astrocyte responses during HAND-associated neuroinflammation, they will: provide innovative insight into the tetraspanin/integrin neuronal signaling, have broader implications for inflammatory diseases that involve MMP/TIMP imbalance and obtain critical proof-of-concept data for future therapeutic strategies relevant to HAND.
HIV-1-associated neurocognitive disorders (HAND) afflict an estimated 69% of HIV-seropositive (HIV+) individuals world-wide, despite the availability of effective antiretroviral therapy. These neurological complications are characterized by cognitive, behavioral and motor dysfunctions, for which successful treatments or prevention remain elusive. A pathological hallmark of all neuroinflammatory conditions is reactive astrogliosis, or the recruitment to and proliferation of astrocytes at the site of injury, which is observed in area of inflammation in HAND. The mechanism by which astrocytic neuroprotective responses are altered during neuroinflammation and their contribution to disease is intriguing and is the primary focus of our and investigation. These studies will lead to a better understanding of the specific mechanistic contributions of astrocytes to HIV-1-neuropathogensis and neuroinflammation.
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