Develop technologies for assessment of aortic aneurysms prone to rupture or dissection. Thoracic and abdominal aortic aneurysms (TAA and AAA) are life threatening conditions that comprise the thirteenth leading cause of death in the United States. For both TAAs and AAAs, monitoring the size of the aneurysm is the only determinant currently used to project the need for elective surgery and to avoid dissection or rupture. However, the size of the aneurysm is not a reliable predictor of aneurysms that are prone to rupture or dissection. Therefore, we propose to test whether circulating microfibril fragments can serve as biomarkers to profile the status and progression of aortic aneurysmal disease. We have already developed unique immunoassays (sandwich ELISAs) that can quantitate 4 fragments of fibrillin-1, 3 fragments of fibrillin-2, and 1 fragment of fibulin-4. These proteins are the major contributors to microfibril structure and function in the aortic elastic lamellae. Preliminary data demonstrate feasibility of using these assays to identify microfibril biomarker profiles for aortic aneurysms. Assays to measure other connective tissue protein fragments (e.g., the crosslinked telopeptides of collagen I and the endostatin domain of collagen XVIII) were based on the prior isolation of the fragments from serum or urine and the subsequent development of specific immunoassays. In contrast, our approach relies upon the exquisite specificities of monoclonal antibodies to detect fragments that are so far uncharacterized. Preliminary data indicate that this approach can identify novel biomarkers associated with Marfan syndrome (fibrillin-2 fragment 72-143) and aortic aneurysm (fibrillin-2 fragment 48-60) and can reveal signature biomarker profiles of aortic aneurysm (reduced fibrillin-1 fragments and increased fibrillin-2 fragments). We propose to use results from proposed studies of human and mouse Marfan syndrome as a wedge to gain insight into the mysteries of common types of aortic aneurysms. The Marfan syndrome, caused by mutations in the gene for fibrillin-1, is responsible for around 5% of all thoracic aortic aneurysms. With 1,100 plasma samples from individuals with aortic aneurysm (100 of these are Marfan), we will test the hypothesis that distinct fibrillin-1 and fibrillin-2 profiles, and possibly fibulin-4 profiles, will distinguish TAA from AAA. We will also use a new mouse model of Marfan syndrome to test whether profiles of circulating microfibril fragments can predict when aneurysms are prone to dissection and rupture and can monitor effects of treatment protocols to attenuate aortic disease progression. Results will quantitate threshold concentrations of circulating microfibril fragments required for dissection and rupture. If successful, our studies will greatly impact the medical management of aneurysmal disease and will lead to new research directions in this area.
For both thoracic and abdominal aneurysms, life threatening conditions, close monitoring of aneurysm size is the only way currently available to determine when to intervene with elective surgery or endovascular repair to avoid dissection or rupture. However, size is not a reliable predictor so new technologies are needed. We propose to meet this Challenge by testing whether circulating microfibril fragments can serve as biomarkers to reliably profile and monitor aneurysmal disease and identify aneurysms that are prone to dissection or rupture.
| Marshall, Lynn M; Carlson, Eric J; O'Malley, Jean et al. (2013) Thoracic aortic aneurysm frequency and dissection are associated with fibrillin-1 fragment concentrations in circulation. Circ Res 113:1159-68 |
| Sengle, Gerhard; Tsutsui, Ko; Keene, Douglas R et al. (2012) Microenvironmental regulation by fibrillin-1. PLoS Genet 8:e1002425 |
| Charbonneau, Noe L; Carlson, Eric J; Tufa, Sara et al. (2010) In vivo studies of mutant fibrillin-1 microfibrils. J Biol Chem 285:24943-55 |
