The latest statistics on the world epidemic of AIDS & HIV report that are at least 40 million people are infected with HIV with nearly 6 million cases of AIDS world-wide. There is a strong correlation between chronic drug use and increase susceptibility to HIV infection. Chronic drug users accounts for approximately a third of all cases of AIDS in the USA and the progression to AIDS dementia and NeuroAIDS is markedly accelerated in opiate drug abusers. To date, heroin next to oxycontin, is the most abused opioid with an estimated 1,000,000 hardcore users in the United States. In addition to increase susceptibility to opportunistic infections a significant number of heroin addicts present with compounding non-healing wounds. Interestingly, a high incidence of delayed wound healing and wound complications has also been documented in the HIV population. Although, both chronic opioid use and HIV infection lead to severe immune compromise, the underlying mechanisms behind the observed delay in wound healing and wound complications in heroin-addicted patients or HIV patients has not been investigated. Neither is there any data showing if combination of drug abuse and HIV infections result in an exacerbated wound healing process. The central hypothesis of this proposal is that chronic morphine treatment will result in a significant delay in wound healing and HIV infection will further exacerbate the healing process, resulting in a greater delay in the wound repair process with more pronounced wound complications. We further hypothesize that opioid drug abuse in the context of HIV infection will reduce bacterial clearance at the wound site, increase dissemination into systemic sites and accelerate the progression to sepsis. We show in our preliminary data that in a mouse model, chronic morphine treatment results in a significant delay in wound healing. In this proposal we will in Specific Aim 1: Investigate if a) morphine treatment delays wound healing and if HIV proteins further exacerbate the wound healing process and b) we will identify the mechanisms by which chronic morphine treatment delays wound repair and if HIV proteins synergizes or additively modulate these mechanisms.
In Specific Aim 2 : We will investigate if morphine withdrawal modulates wound healing and if HIV proteins TAT and GP+120 further exacerbate the healing events in morphine withdrawn animals.
In Specific Aim 3 : We will investigate the effect of chronic morphine and morphine withdrawal on wound remodeling following wounding and if HIV proteins, TAT and gp-120 exacerbate these effects. Experiments in Aims: 1-3 will use WT, MORKO and TAT transgenic mice + gp120 protein. Our long-term goal is to identify the mechanisms by which opiate drug abuse contributes to immunosuppression and susceptibility to infection in HIV infected patients and to develop therapeutic strategies aimed at decreasing wound complications and facilitate the healing process. ? ? ?
|Wang, Fuyuan; Roy, Sabita (2017) Gut Homeostasis, Microbial Dysbiosis, and Opioids. Toxicol Pathol 45:150-156|
|Moidunny, Shamsudheen; Matos, Marco; Wesseling, Evelyn et al. (2016) Oncostatin M promotes excitotoxicity by inhibiting glutamate uptake in astrocytes: implications in HIV-associated neurotoxicity. J Neuroinflammation 13:144|
|Meng, Jingjing; Roy, Sabita (2016) Study of Epithelium Barrier Functions by Real-time TER Measurement. Bio Protoc 6:|
|Banerjee, S; Sindberg, G; Wang, F et al. (2016) Opioid-induced gut microbial disruption and bile dysregulation leads to gut barrier compromise and sustained systemic inflammation. Mucosal Immunol 9:1418-1428|
|Ninkovic, Jana; Jana, Ninkovic; Anand, Vidhu et al. (2016) Differential effects of gram-positive and gram-negative bacterial products on morphine induced inhibition of phagocytosis. Sci Rep 6:21094|
|Dutta, Raini; Roy, Sabita (2015) Chronic morphine and HIV-1 Tat promote differential central nervous system trafficking of CD3+ and Ly6C+ immune cells in a murine Streptococcus pneumoniae infection model. J Neuroinflammation 12:120|
|Meng, Jingjing; Banerjee, Santanu; Li, Dan et al. (2015) Opioid Exacerbation of Gram-positive sepsis, induced by Gut Microbial Modulation, is Rescued by IL-17A Neutralization. Sci Rep 5:10918|
|Sindberg, Gregory M; Sharma, Umakant; Banerjee, Santanu et al. (2015) An infectious murine model for studying the systemic effects of opioids on early HIV pathogenesis in the gut. J Neuroimmune Pharmacol 10:74-87|
|Chanakira, Alice; Kir, Devika; Barke, Roderick A et al. (2015) Hypoxia Differentially Regulates Arterial and Venous Smooth Muscle Cell Migration. PLoS One 10:e0138587|
|Banerjee, Santanu; Ninkovic, Jana; Meng, Jingjing et al. (2015) Morphine compromises bronchial epithelial TLR2/IL17R signaling crosstalk, necessary for lung IL17 homeostasis. Sci Rep 5:11384|
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