Dr. Tilson examines electrophoresis results implicating a new protein in aneurysm development.

Another area of interest in the SLR Research Laboratory is the creation of novel AAA animal models. A complete animal care facility is available along with a miniature rodent intensive care unit to assure that results are standardized and measurements consistent. The two pictures demonstrate rodent microsurgery with the aorta exposed via a transabdominal approach. The picture on the left demonstrates the renal arteries while the picture on the right exemplifies the reflection of the transverse colon needed to expose the murine aorta.

The picture on the left shows normal smooth muscle architecture in a murine aorta. The right picture demonstrates a disordered structure found in a genetic knock-out mouse. Investigations have thus far evaluated genetically predisposed animals (blotchy,Apoe -/-), post-stenotic dilatation, elastase infusion (Anidjar-Dobrin model), and periarterial calcium chloride. New models employing novel infusion techniques are currently under evaluation.

Collagen XI (Col XI) is a candidate gene for a locus of susceptibility to abdominal aortic aneurysms (AAAs). An alternatively spliced isoform containing Exon 6A is known to be expressed in arteries (versus 6B in cartilage). Laboratory work has implicated that the mRNA of Collagen XI alpha-1 (Col XI a-1) is over-expressed 19-fold by adventitial fibroblasts cultured from aortic aneurysm (versus normal aortic fibroblasts).

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Annals of the New York Academy of Sciences, vol. 1085, 2006

• Tilson MD, Ro C: The Candidate Gene Approach to Susceptibility for Abdominal Aortic Aneurysm (AAA): TIMP1, HLA-DR-15, Ferritin Light Chain (FTL), and Collagen XI-Alpha-1 (COL11A1.
• Tilson MD: Features and Genomic Origins of Matrix Cell Adhesion Molecues 1 and 2 (Mat-CAM-1 and Mat-CAM-2) Expressed by Fibroblasts of Human Aortic Adventitial Origin.
• Tilson MD, Withers L.: Arterial Aneurysms in HIV Patients. Molecular Mimicry Versus Direct Infection?

Revisions to three GenBank Flatfiles, December 2006

The first two revisions are simple, and the flatfiles of the reported nucleotide sequences are unchanged. The revisions update our recent interpretations of the biological significance of the sequences.

• Cytochrome b mutation. A mutation in a mitochondrial DNA may explain maternal transmission of AAA susceptibility. In 2001 we reported a sequence for cytochrome b, from a cDNA library derived from aortic fibroblasts of a patient with AAA. The sequence has a deduced premature STOP codon Trp[33]X. Ever since 1994, when I wrote a paper (with Margreta Seashore of Yale Univ) on patterns of clustering of affected AAA patients in families, I have been perplexed by a phenomenon which we described at the time as "X-linked Dominant Inheritance" (for lack of a more definitive term). We know now that cytochrome b is a mitochondrial DNA sequence, so that it would be inherited by all children of a mother with AAA. In the context of increasing interest in oxidative injury as a component of AAA pathobiology, and of new knowledge about the role of the mitochondrion in inducing pathways to apoptosis, the observation of mutation in cytochrome b takes on a novel potential interest. If a dud cytochrome b interferes with electron transfer by Complex III, the mitochondrion might be showering the cytoplasm of the aortic adventitial fibroblast with free radicals. A title under consideration for a manuscript in preparation is "Trp[33]X Mutation May Explain the So-Called 'Black Widow' Syndrome"
• Matrix Cell Adhesion Molecule-1 (MatCAM-1) This revision is to the title of a manuscript in preparation (tagged "unpublished"). based on the sequence of Matrix Cell Adhesion Molecule-1 (MatCAM-1). We now understand that the N-terminal domains of some Ig-like repeats in members of the cadherin family of cell-cell adhesion molecules feature reactive tryptophan residues in the loops exposed at the turns of the anti- parallel folds of the Ig-sheets. These residues are involved in domain switching across cells to establish adhesion in contiguities like desmosomes. We now observe that there is a "W" in a loop near the N-terminus of Mat-CAM-1. We also have immunohistochemical evidence that the C-terminal domain is anchored in the matrix of the adventitial collagen/elastin associated microfibrils of trhe aortic adventitia. Thus, the "W" in the Mat-CAM-1 may enable a switch-domain to bind to a cellular cadherin, providing a biochemical basis for matrix <-> cell adhesion. A title under consideration for a manuscript in preparation is "Trp (16) in Precursor mRNA sequence for Matrix Cell Adhesion Molecule-1 (Mat-CAM-1) May Provide An Additional Basis for Adhesion to Cell-Surface Cadherins".
• Mutations of Collagen XI-alpha-1 These revisions involve several sequences with possible mutations in the aorta-specific, alternatively- spliced, Exon 6A of Collagen XI-alpha. From the initial sequencing data on the genomic DNA from specimens with AAA, the computer analytical program read several heterozygous polymorphisms, which we confirmed by visual inspection of the chromatographic runs. This work was repeated by my Post-Doctoral Student Charles Ro (2004-2005), who used primers that were more widely spaced to include the flanking introns of Exon 6A. The sequence data were of much higher quality and led to the conclusion that we had misinterpreted the initial apparent heterozygosities in Exon 6A. However, on those runs, there was an unambiguous substitution upstream in the intron preceding 6A in consecutive patients. This polymorphism may be in a promotor region. We are presently updating all previously reported Exon 6A sequences; and in addition, we are reporting sequences from new specimen acquisitions that exhibit the same.

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Ultrasound scanning equipment including anesthesia circuit, US probe, and monitor.

Gross dissection of normal aortic anatomy