Clayton A. Wiley, MD, PhD
Professor of Pathology
PERF Endowed Chair
Dr. Wiley is Director of the Division of Neuropathology. In addition to clinical sign out, Dr. Wiley directs the Neuropathology fellowship program and runs an NIH funded research program studying neuroinflammation and viral encephalitis in particular.
UPMC Presbyterian Hospital
M8741 South Tower
200 Lothrop Street
Pittsburgh, PA 15213
Office Telephone: 412-647-0765
Email Address: email@example.com
- MD - University of California, San Diego, 1981
- PhD - University of California, San Diego 1981
Research InterestsKeywords: Encephalitis, Viral infection, Macrophages / microglia, Innate immune response, Inflammation
The overarching theme of our laboratory is the role of neuroinflammation in mediating neurodegeneration.
Biomarkers of Neuroinflammation
In the recent past we have collaborated with the Positron Emission Tomography (PET) Center to image macrophage activation in human and non-human primate models of neurological disease. Using a novel radioligand (PK11195) to assess activated microglia in brains of living HIV-infected human and SIV-infected primates, these studies demonstrated the feasibility, but limited sensitivity of PK11195 PET in monitoring CNS inflammation (Venneti et al., 2008; Venneti et al., 2004; Venneti et al., 2009; Wiley et al., 2009).
While performing the PET studies, we took advantage of the study's serial time points to discover biomarkers of neuroinflammation in serum and CSF. Using unbiased proteomic analysis with SELDI-TOF mass spectrometry, we discovered a highly sensitive and reproducible biomarker of CNS inflammation, Chitinase 3-like 1 protein (CHI3L1). We and other groups have since observed expression of CHI3L1 in a broad spectrum of CNS inflammatory diseases (Alzheimer's disease (AD), traumatic brain injury (TBI), Multiple sclerosis (MS) etc.) (Bonneh-Barkay et al., 2010).
Control of neuroinflammation
While of great utility as a biomarker, CHI3L1 is becoming even more important as a member of a new class of proteins mechanistically involved in the control of neuroinflammation. These novel proteins modulate the interaction between inflammatory cells and CNS extracellular matrix. Using transgenic mice where the mouse homolog of CHI3L1 was deleted by homologous recombination, we have examined the role of this protein in animal models of MS (EAE) and TBI (Bonneh-Barkay et al., In Press; Wiley et al., under review 2012). In both models, deletion of CHI3L1 led to worse clinical and pathological outcome. Current studies in our lab are aimed at elucidating the molecular mechanism by which CHI3L1 limits inflammation and how to mimic its action using small molecules. These studies hold the potential of developing novel therapies to decrease neuroinflammation, potentially supplementing or synergistically interacting with current anti-inflammatories.
Age related neurodegeneration
While intuitively obvious, it warrants remembering that the single most important determinant of neurodegeneration is age. Through extensive collaborations with the Alzheimer's Disease Research Center, we clinically document the neuropathology of AD and related diseases. The beta amyloid hypothesis of AD proposes that toxic fragments or oligomers of beta amyloid mediate neurodegeneration. We and others have explored the capacity of active immunization to eliminate beta amyloid from the aging primate brain (Kofler et al., 2012). Current studies in the lab are examining how lentiviral infection and combined anti-retroviral therapy modulate age related neurological processes and gene expression associated with neurodegeneration.
Collaborations with other Pittsburgh investigators have allowed us to expand our studies of the brain's susceptibility to viral infections. Working with Drs. Ted Ross and Doug Reed, we have discovered the heightened susceptibility of the brain to aerosol transmission of common viral pathogens. Arboviruses that normally infect through insect vectors cause limited systemic disease, but when delivered through aerosol route, they rapidly cause lethal encephalitis. How the brain's innate immune response and systemic adaptive immunity protect the CNS is a current focus of the lab. In collaboration with Dr. Ross, we have discovered that host exposure to seasonal influenza determines susceptibility to lethal avian influenza. Newly proposed studies will elucidate the role of CD8 T-cells in conferring this protection. Importantly from a public health perspective, this team is also researching how immunization protects or predisposes to encephalitis.
Selected PublicationsView Dr. Wiley's publications on PubMed
Kofler J and Wiley CA; Microglia: Key innate immune cells of the brain. Toxicologic Pathology 39:103-114, 2011. PMID: 21078923
Wiley CA, Carter DM, Ross TM, Bissel SJ; Absence of fetal transmission of H1N1 despite severe maternal infection. Influenza and other Respiratory Viruses 2011 Nov 22. doi: 10.1111/j.1750-2659.2011.00310.x. [Epub ahead of print] PMID:22103260
Bonneh-Barkay D, Bissel SJ, Kofler J, Starkey A, Wang G, Wiley, CA; Astrocyte and macrophage regulation of YKL-40 expression and cellular response in neuroinflammation. Brain Pathology 2011 doi: 10.1111/j.1750-3639.2011.00550.x
Wiley CA, Murdoch G, Parwani A, Cudahy T, Wilson D, Payner T, Springer K, Lewis T; Interinstitutional and interstate teleneuropathology. Journal of Pathology Informatics, 2011 10.4103/2153-3539.80717
Giles BM, Bissel SJ, Craigo JK, Dealmeida DR, Wiley CA, Tumpey TM, Ross TM; Elicitation of Anti-1918 Influenza Virus Immunity Early in Life Prevents Morbidity and Lower Levels of Lung Infection by 2009 Pandemic H1N1 Influenza Virus in Aged Mice. J Virol. 2011 Nov 30. [Epub ahead of print] PMID:22130546 [PubMed - as supplied by publisher]
Giles B, Bissel S, DeAlmeida D, Wiley C, Ross T: Antibody breadth and protective efficacy is increased by vaccination with computationally optimized hemagglutinin but not with polyvalent hemagglutinin based H5N1 VLP vaccines. Clinical and Vaccine Immunology 2011 Dec 21. [Epub ahead of print]
Bissel SJ, Giles BM, Wang G, Olevian DC, Ross TM, Wiley CA. Acute Murine H5N1 Influenza A Encephalitis. Brain Pathol (2012) 22(2):150-158. PMCID: PMC3204170
Clark KH, Wiley CA and Bradberry CW: Psychostimulant abuse and neuroinflammation: Emerging evidence of their interconnection. In Press Neurotoxicity Research
Kofler J, Lopresti B, Janssen C, Trichel AM, Masliah E, Finn OJ, Salter RD, Murdoch GH, Mathis CA and Wiley CA: Preventive immunization of aged and juvenile non-human primates to beta-amyloid. J Neuroinflammation (2012) 9:84.
Bonneh-Barkay D, Wang G, LaFramboise WA, Wiley CA and Bissel SJ: Exacerbation of experimental allergic encephalomyelitis in the absence of breast regression protein-39/chitinase 3-like-1. J Neuropathology and Experimental Neurology (2012) 71:948-958.