The long-term objective is to characterize mechanisms by which a host-derived protein called PINCH promotes neuronal fitness in response HIV infection of the CNS with the overall goal to understand PINCH's role in neurons exposed to viral and inflammatory factors. Synaptodendrtic injury correlates closely with the presence and severity of cognitive impairment in HIV patients. Since synaptodendritic damage in HIV infection of the brain is partially reversible and can occur in the absence of significant neuronal loss, information gained from these studies will enhance our ability to improve therapies to treat HIV infection of the brain and alleviate neurological complications observed in many HIV patients. In the brains of HIV infected individuals, PINCH is expressed exclusively by neurons showing signs of synaptodendritic damage. PINCH is an adapter protein that mediates bidirectional signal transduction between the extracellular matrix and intracellular networking pathways via interactions with integrin linked kinase (ILK) and Nck2. Thus, our overall hypothesis is that in response to disruptions in neuronal signaling caused by HIV infection of the CNS, PINCH protein is stabilized by sumoylation to promote proper interactions with ILK and Nck2. We propose two AIMS that investigate in vitro I) mechanisms by which PINCH expression is regulated, and II) the biological consequences of PINCH expression on neurons exposed to viral protein and host inflammatory factors produced during HIV infection of the CNS. Primary neurons treated with TNF-a or Tat to mimic some aspects of HIV infection of the brain will be assessed for PINCH expression via qRT-PCR, and Northern and Western analyses, and by siRNA knockdown. Sumoylation of PINCH will be assessed by reciprocal IP and Western analyses after exposure to TNFa and/or Tat. We further hypothesize that disruptions in PINCH's normal communication with ILK and Nck2 may diminish neuronal recovery. Neurons exposed to TNFa and/or Tat will be assessed for ILK and Nck2 expression and functional interactions with PINCH. To address biological consequences of PINCH in the context of HIV infection of the CNS, site-directed mutagenesis, PINCH protein accumulation and MALDI-TOF analyses will be used. Expanded studies of HIV patients'brains with MCMD, HIVE, dementia and importantly HAND in the absence of HIVE as well as HIV patients who died without CNS complications will be analyzed via laser capture microdissection of neurons and MALDI-TOF analyses will also be conducted.

Public Health Relevance

Public Health Relevance

HIV patients are much living longer due to effective anti-HIV medications. Anti-HIV medications are less effective at treating HIV in the brain. So, many HIV patients suffer from neurological impairments. In this context, PINCH protein may contribute to neuron recovery during HIV infection of the brain. Understanding mechanisms by which PINCH functions will contribute to improved therapies to protect the brain from damage by HIV, and may improve the quality of life in HIV patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH085602-05
Application #
8416991
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Joseph, Jeymohan
Project Start
2009-05-01
Project End
2014-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2013
Total Cost
$338,580
Indirect Cost
$112,860
Name
Temple University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Adiga, Radhika; Ozdemir, Ahmet Y; Carides, Alexandra et al. (2014) Changes in PINCH levels in the CSF of HIV+ individuals correlate with hpTau and CD4 count. J Neurovirol 20:371-9
Ozdemir, Ahmet Yunus; Rom, Inna; Kovalevich, Jane et al. (2013) PINCH in the cellular stress response to tau-hyperphosphorylation. PLoS One 8:e58232
Kovalevich, Jane; Tracy, Brittany; Langford, Dianne (2011) PINCH: More than just an adaptor protein in cellular response. J Cell Physiol 226:940-7
Jatiani, Asavari; Pannizzo, Paola; Gualco, Elisa et al. (2011) Neuronal PINCH is regulated by TNF-ýý and is required for neurite extension. J Neuroimmune Pharmacol 6:330-40
Rearden, Ann; Hurford, Rosemary; Luu, Nhan et al. (2008) Novel expression of PINCH in the central nervous system and its potential as a biomarker for human immunodeficiency virus-associated neurodegeneration. J Neurosci Res 86:2535-42