Description of Research:
Research Description: During the past ten years, dramatic advances have been made in unraveling the biological bases of age-related macular degeneration (AMD), the most common cause of irreversible blindness in western populations. In that timeframe, two distinct lines of evidence emerged from this laboratory that implicated chronic local inflammation and activation of the complement cascade in AMD pathogenesis. First, a number of complement system proteins, complement activators, and complement regulatory proteins were identified as molecular constituents of drusen, the hallmark extracellular deposits associated with early AMD. Subsequently, genetic studies revealed highly significant statistical associations between AMD and variants of several complement pathway-associated genes including: Complement factor H (CFH), complement factor H-related 1 and 3 (CFHR1 and CFHR3), complement factor B (CFB), complement component 2 (C2), and complement component 3 (C3). Thus, it i
s now apparent that dysregulation of the complement cascade, and of the alternative pathway in particular, is a critical early predisposing step in the development of AMD, regardless of ocular phenotype.
Although the initiating event(s) that gives rise to retina-RPE-choroid pathology in AMD remains elusive, a plethora of different insults have been proposed as causative. Narrowing this list to the most critical element(s) is among the greatest remaining future challenges in AMD research. Irrespective of the precise triggering event(s) that provokes RPE-choroid pathology, however, it is clear that a major downstream consequence is the deposition and sequestration of cellular and acellular debris in the sub-RPE space. Failure to dispose of the entrapped debris may be sufficient in itself to trigger a “nucleation event”, generate a local pro-inflammatory signal, and activate the complement system in an attempt to eliminate the debris. For those who lack sufficient alternative pathway complement modulating activity, this would most likely result in sustained complement attack, bystander injury to neighboring cells, continuing formation of drusen and other sub-RPE deposits, p
hotoreceptor degeneration and, eventually, concomitant loss of vision.
Most recently, we designed a series of translational studies to clarify the role of the complement system in the pathogenesis of AMD. Dr. Hageman is the Principal Investigator of a NIH R24-funded research program designed to address these aims. The program represents a collaborative effort among cell biologists, molecular immunologists, geneticists, microbiologists, ophthalmologists, and pathologists, many of whom are established investigators in the AMD field. The studies undertaken in this program are designed to test the central hypothesis that quantitative changes or functional alteration(s) in CFH and other complement-related proteins result in uncontrolled complement activation and bystander injury to ocular cells, resulting in progressive retinal degeneration and concomitant loss of vision. The research program is organized into six interrelated Modules. Module I is directed toward the expansion of our existing repositories of eye tissues, bloods, sera, urine, RNA, and DNA from donors and well-characterized families and cohorts of patients with AMD, MPGN II, and other potentially related, immune-mediated diseases and the acquisition of relevant biological reagents, tools, and experimental model systems with which to pursue these studies. In Modules II-VI, we employ these resources to solidify our basic understanding of how dysregulation of the alternative pathway, and of CFH in particular, confers increased susceptibility to AMD and other diseases. Our current understanding of the role of the complement system in the AMD disease process has now been refined to the point where new therapeutic approaches can be envisioned that are designed to restore the complement-modulating activity that is deficient in genetically susceptible individuals. As such, modules V-VI relate to the identification of new biomarkers and drug targets that will hasten the development of clinically effective diagnostics and pharmaceuticals for the treatment of AMD.
In its simplest form, one therapeutic approach would be to augment the native form of CFH in ‘at-risk’ individuals with a supplemental source of ‘protective’ CFH that would modulate the ongoing complement attack, attenuate the local inflammation, and thereby delay the onset and slow the progression of the disease. In order to establish ‘proof of concept’ for this new paradigm -- with the overall goal of hastening the translation of these new findings into a viable new therapeutic treatment -- we are examining the effect of liver transplantation on the development and progression of ocular changes characteristic of AMD in patients over the age of 55.
The specific roles that complement and other inflammation-related phenomena play in the development of early AMD are as yet largely unresolved. Questions that are being addressed currently include the following:
• What cellular event(s) leads to complement activation at the RPE-choroid interface? Is complement activation primarily systemic, or is the local system also engaged?
• What are the respective roles of acute phase proteins and pro-inflammatory cytokines in RPE-choroid pathology, and when do they come into play?
• What is the temporal relationship between local inflammation, complement activation, dendritic cell involvement, and drusen biogenesis at the RPE-choroid interface?
• What is the significance of the coagulation cascade in AMD, and of various coagulation and fibrinolytic proteins found in drusen including thrombin, fibrin/fibrinogen, and plasmin/plasminogen? Is coagulation associated with activation of complement via the intrinsic pathway?
• Does the presence of HLA-DR in drusen, and the invasion of drusen by dendritic cells, signify an ongoing process of antigen presentation to the immune system? If so, what are the antigens involved?
• To what extent does the adaptive immune system contribute to the AMD disease process?
• How does one explain the unique susceptibility of the macula to degeneration in the context of established immune-mediated pathways?
Does this research involve human subjects or animals? Yes
If yes, what is the protocol number? Pending
10/2009
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