Investigator:

Rula, A. Hajj-Ali, MD and Gary S. Hoffman, MD

Location:

Center for Vasculitis Care and Research, Cleveland Clinic Foundation Cleveland, Ohio

Timeline:

March 1, 2006 - February 28, 2007

Abstract:

Giant cell arteritis (GCA) is the most common type of vasculitis and affects people with mean age of about 70.Complications include ischemic–occlusive disease leading to blindness, strokes, neurologic dysfunction, and lesions in major arteries. The pathogenesis of vasculitis is incompletely understood. It is uncertain whether selective injury to specific vascular sites is due to primary abnormalities of immune function or abnormalities that first appear within the once normal vessel that “invites” an immunoinflammatory response. Observations in man and experimental models indicate that the vessel wall is not a passive participant in the process of injury, and injured sites are not randomly selected. We hypothesize that the tissue substrate (vessel wall) in GCA plays an important role in disease vulnerability and pathogenesis and that gene expression profile of uninvolved segments of temporal arteries from patients with GCA, will reveal the initial changes that predispose to vasculitis, before overt inflammation occur. Our goals are to characterize the molecular signature that defines vessel targeting and susceptibility for different vascular disease and to identify pathogenic mechanisms in giant cell arteritis. We propose to use microarray techniques to specifically aim to identify differential gene expression patterns of uninvolved segments of temporal arteries from patients with GCA compared to age-, gender and ethnicity- matched control specimens, to validate the data obtained from microarray analysis by using Real Time Quantitative PCR and to Identify the microenvironment where the genes of interest are expressed using RNA in situ hybridization techniques. Differences in gene expression that we identify in the temporal arteries of GCA-affected vs. control temporal arteries should lead to a better understanding of pathogenesis of GCA. These findings will aid to understanding qualities of vascular substrate that influence susceptibilities to other type of systemic vasculitis including Wegener Granulomatosis.

Specific AimsTo determine whether acquired abnormalities within the vessel wall precede and are required for inflammatory injury (i.e. vasculitis) in giant cell arteritis (GCA) of the elderly.

Relevance to Wegener's Granulomatosis

It is uncertain whether selective injury to specific vascular sites is due to primary abnormalities of immune function or abnormalities that first appear within the once normal vessel that “invites” an immunoinflammatory response. The fact that giant cell arteritis affects patients >50 years of age (mean 74) suggests that acquired abnormalities of either the targeted vessels and/or of immune function play a role in pathogenesis. Observations in man and experimental models indicate that the vessel wall is not a passive participant in the process of injury, and injured sites are not randomly elected. For example, GCA has a predilection for the aortic arch, its primary branches, and the cranial vessels that originate from the external carotid artery (e.g. temporal, occipital, maxillary and facial arteries). In contrast, the abdominal aorta and its distal branches are rarely involved. These observations about site predilection argue most strongly for initial change in tissue substrate playing an important role in pathogenesis.

However such patterns and onset in the elderly would not eliminate a role for genetic factors. Indications of genetic factors playing a role in GCA include the observations that women are affected 2-3 times more often than men and individuals of Northern European decent are more commonly affected than others, such as African Americans and Asians, among whom GCA is rare. Patients with GCA also have an ncreased requency of HLA-DR4 alleles. Prior studies, that have evaluated the pathogenesis of GCA, have primarily focused mostly on description of the inflammatory events within the vessel wall. These studies have added a great insight to understanding cell populations and cytokine profiles that play a role in injury. However, the question of why selective vessel targeting occurs or what acquired vessel changes lead to triggering disease in specific vessels has not been addressed. Knowledge of gene expression patterns within the vessel wall in GCA will enhance our understanding of the initial events in the pathogenesis of GCA and will have implications in the pathogenesis of not only of giant cell vasculitis but also in different systemic vasculitides including Wegener Granulomatosis.

Future Plans

The pathophysiology of GCA is poorly understood and efforts to understand this disease are highly appreciated. We are proposing to study the pathophysiology of giant cell arteries in a novel way that address the organ targeting and challenge the long standing paradigm that the initial insult in GCA is immune mediated. The advent of new methodologies like the microarray provide unprecedented opportunities to study the wall of vessels affected by GCA in a comprehensive manner. In addition, complementing these studies with In situ hybridization will reveal the topography of the identified genes. Such methods have not been applied previously in studying this disease. We expect to find differential gene expression profile at initial stage of the disease and complement the data in the future by the differential protein profile which will add a great insight into the understanding of the functional role of the expressed genes. We have taken a careful step in analyzing the data, to include ways to check for PI Name: Hajj-Ali , Rula, A. reproducibility, validity and reliability of the measurements, in order to interpret the results in a meaningful way. In this design we aimed to further validate the data and most importantly to localize the microenvironment of the genes of interest. This proposal represents a pilot study of our future research plans. Once the differentially expressed genes have been identified and organized into functional groups or “clusters”, the implications of these gene expression changes need to be addressed. The second tier of studies will allow us to determine whether the gene expression changes identified are initial triggering events, secondary changes or late compensatory changes. We will employ functional proteomic analysis to investigate proteins that interacts with specific genes of interest.

The localization of the cellular microenvironment or structure where the differentially expressed genes will emerge will serve as the basis for specific evaluation of this structure or cellular element in the pathogenesis of GCA.

Identification and characterization...

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