Age and aging-related comorbidities are among the major risk factors for the development of cognitive disorders. As the population ages, the prevalence and burden of cognitive impairment on public health is expected to increase dramatically. One segment of the aging population that is both rapidly expanding and increasingly vulnerable to cognitive dysfunction is persons with human immunodeficiency virus (HIV)-infection. Despite the use of highly active antiretroviral therapy (HAART), the central nervous system (CNS) is vulnerable to HIV infection and the incidence significantly increases in older adults. Despite the significance of this clinical problem, surprisingly little basic science research has been done to understand contribution of aging to the pathogenesis of HIV-associated neurocognitive disorder (HAND). One of the potential mechanisms by which aging may contribute to age- and HIV-related neuropathology is via astrocyte senescence. Astrocytes perform a myriad of complex functions in the central nervous system to maintain neuronal homeostasis and are also capable of initiating a senescence program in vitro. Senescence is classically defined as an essentially irreversible proliferative growth arrest that is telomere-based, but it can also be induced by stress. Cells displaying biomarkers of senescence have been found in tissue biopsies of aged animals and humans;however little is known about the potential appearance of senescent cells in the brain. The selective clearance of cells expressing the senescence biomarker p16INK4a in a mouse model of premature aging delayed and alleviated age-related pathologies in several organ systems. These findings implicate senescent cells in age-related tissue dysfunction and suggest that interventions to prevent the initiation of the senescence phenotype or to target the removal of senescent cells would be both relevant and beneficial in the aging population. Given the complexity and heterogeneity of the molecular mechanisms underlying the senescence response depending upon cell type, this proposal will examine the effect of HIV-1 envelope glycoprotein gp120 on the production of a senescence-associated secretory phenotype (SASP) and activation of the major senescence signaling pathways: p38MAPK, p53-p21, and p16INK4a-Rb in astrocytes. In addition, the consequences of senescence on aspects of brain functioning related to astrocytes will be investigated through the use of an in vitro co-culture model of the blood-brain barrier (BBB). Indices of BBB integrity such as transendothelial electrical resistance (TEER), tight junction protein expression and localization, restriction of the passage of a fluorescently-conjugated tracer molecule as well as the level monocyte migration through the barrier will be evaluated to determine the effect of astrocyte senescence on these parameters. The long term goal of this project is to understand the role of senescence in HAND and to determine whether factors modulating the onset of astrocyte senescence and production of a SASP have potential therapeutic benefits for HAND and aging.
Despite the successes of antiretroviral therapy in transforming HIV infection into a chronic disease, neurological complications affect up to fifty percent of the HIV-1 positive population and remain a major clinical problem especially in the context of aging. This proposal seeks to better understand how viral factors induce dysfunction in the brain with the long-term goal of identifying novel therapeutic targets for this condition and other aging-related neurological diseases. This research training will allow me to gain the necessary experience to pursue a career as physician-scientist in the field of HIV-related neuropathology and to obtain a faculty position at a major academic research center.
|Crowe, Elizabeth P; Nacarelli, Timothy; Bitto, Alessandro et al. (2014) Detecting senescence: methods and approaches. Methods Mol Biol 1170:425-45|
|Bitto, Alessandro; Lerner, Chad A; Nacarelli, Timothy et al. (2014) P62/SQSTM1 at the interface of aging, autophagy, and disease. Age (Dordr) 36:9626|