Plasma Levels of Matrix Metalloproteinases (MMPs) and Degree of DNA Fragmentation in Pseudoexfoliation (PEX) Glaucoma
Condition: Pseudoexfoliation Syndrome; Glaucoma
MeSH terms: Glaucoma; Exfoliation Syndrome; Syndrome
Study type: Observational

Summary: 
      Glaucoma is a worldwide leading cause of blindness. The key feature of this ocular neuropathy
      is characterized by an excavating optic nerve head. Loss of retinal ganglion cells is the
      final end point in blinding diseases of the optic nerve such as glaucoma. It is known that
      neuronal cell death in glaucoma occurs by apoptotic mechanism. In earlier studies, the
      investigators demonstrated that the process of apoptosis is reflected in circulating
      leukocytes by different parameters, like differential messenger ribonucleic acid (mRNA)
      expression and an increased fragmentation of the deoxyribonucleic acid (DNA). Such
      alterations point out a relationship between cellular stress and apoptotic events.

      Based on the results of mRNA-expression, the investigators also expect alterations on the
      protein level.

      This study is, therefore, designed to characterize the proteome related to the proteins
      involved in cell death related pathways.

      Thus the expression pattern of several proteins in leukocytes from patients with primary open
      angle glaucoma will be analyzed by techniques like Western-blot and tandem mass spectrometry.
      These samples will be compared with healthy controls. In addition, they will be also compared
      with samples from patients with Parkinson's disease. Since glaucoma is a neurodegenerative
      disease, these patients will be included as a positive control in this study.
    

Detailed description: 
      Hypothesis:

      Subjects with pseudoexfoliation syndrome in combination with glaucoma may have an altered
      activity of plasma matrix-metalloproteinase activity and a higher degree of DNA fragmentation
      in the leukocytes.

      Specific aims:

      Determination of the level of plasma matrix-metalloproteinase activity and of the degree of
      DNA fragmentation of leukocytes in patients with pseudoexfoliation syndrome glaucoma (PEX) in
      comparison to patients with primary open angle glaucoma (POAG).

      Background:

      One of the main pathogenic factors for the development of glaucoma is an increased
      intraocular pressure (IOP), which leads to a direct or indirect damage of the nerve fibers in
      the area of the optic disk. The raise of IOP is based on the increased outflow resistance of
      the trabecular meshwork due to an excessive accumulation of extracellular material in the
      juxtacanalicular tissue of the meshwork in eyes with primary open-angle glaucoma (POAG), and
      an impaired turnover of the trabecular meshwork matrix, which is of paramount importance to
      the regulation and maintenance of aqueous humor outflow.

      Pseudoexfoliation (PEX) syndrome is a systemic disorder of the extracellular matrix, which
      represents the most common identifiable cause of open-angle glaucoma. There is increasing
      evidence suggesting that PEX syndrome may be a type of fibrosis associated with excessive
      synthesis and deposition of an abnormal elastic fibrillar material in many intra- and
      extraocular tissues. Active involvement of the trabecular meshwork in this abnormal matrix
      process leading to progressive accumulation of PEX material in the juxtacanalicular tissue is
      considered to be the primary cause of chronic pressure elevation in eyes with PEX syndrome.
      However, the mechanisms responsible for this aberrant matrix process remain unknown.
      Excessive production and accumulation of abnormal matrix components may be due to increased
      de-novo synthesis, decreased turnover of matrix components, or both.

      Extracellular matrix turnover is mediated by matrix metalloproteinases (MMPs), a large family
      of endopeptidases with variable substrate spectra, the presence of which has been described
      in human aqueous humor.

      The activity of these enzymes is regulated in part by specific endogenous inhibitors, the
      tissue inhibitors of metalloproteinases (TIMPs). Dysregulated expression of MMPs and TIMPs
      has been implicated in many disease processes accompanied by abnormal matrix production, such
      as fibrotic disorders, and a variety of other disease states. In the eye, abnormal expression
      of MMPs has been implicated, among many other disorders, in glaucoma, in proliferative
      vitreoretinopathy, secondary cataract formation, and the pathogenesis of pterygia. Therefore,
      MMPs and TIMPs are likely candidates to be involved in the abnormal extracellular matrix
      metabolism characteristic of PEX syndrome/glaucoma (PEXG) and POAG.

      PEX seems to be an independent risk factor for glaucoma. Possibly, this may be due to an
      altered perfusion. So, PEX syndrome represents not only the most common identifiable cause of
      open-angle glaucoma, but also a risk factor for cardiovascular diseases. PEX syndrome and
      iris trans-illumination defects are seen in patients with transient ischemic attacks. At the
      microcirculatory level, ischemia/reperfusion (I/R) injury is thought to be initiated by
      chemotactic accumulation of circulating leukocytes, their activation and interaction with the
      endothelium of postcapillary venules. In addition, oxygen free radicals are thought to play a
      pivotal role in the pathogenesis of I/R injury. A variety of experimental models of ischemic
      injury have shown that free radicals induce post-ischemic oxidative damage to DNA. Although
      several human studies have revealed that oxygen radicals generated by other mechanisms like
      irradiation, only few data exist that demonstrate the influence of reperfusion-associated
      oxygen radicals on DNA in humans. We hypothesize that the pathogenic processes in PEX may be
      reflected in leukocytes.

      Depending on the results that glaucoma patients differ on the level of their mRNA expression
      for various MMPs in peripheral leukocytes and that PEX syndrome is often seen with transient
      ischemic attacks, we assume differences in the activity of MMPs in the plasma as well as
      changes in the DNA stability in peripheral leukocytes of patients with PEX glaucoma.

      This study is, therefore, designed to analyze the activity of gelatinases (MMP-2 and -9) in
      plasma and the degree of DNA fragmentation in peripheral leukocytes of patients with PEX
      syndrome and PEXG compared to POAG and controls.
    

Observational model: Case-Only
Time perspective: Prospective
Sampling method: Non-Probability Sample
Study population: 
        Patients with pseudoexfoliation
      
Keywords: PEX; glaucoma; MMP; DNA degradation; POAG; Healthy subjects