2 results
340 The Effects of PTSD-Dependent Neurogenic Hypertension and Inflammation on Thoracic Aortic Aneurysm Progression
- Part of
- Heather Holman, Sara Sidles, Ying Xiong, Jennifer Rinker, Jean Marie Ruddy, Amanda LaRue, Rupak Mukherjee, Jeffrey Jones
-
- Journal:
- Journal of Clinical and Translational Science / Volume 7 / Issue s1 / April 2023
- Published online by Cambridge University Press:
- 24 April 2023, p. 101
-
- Article
-
- You have access Access
- Open access
- Export citation
-
OBJECTIVES/GOALS: Nearly all thoracic aortic aneurysm patients suffer from hypertension leading to elevated wall tension and abnormal extracellular matrix remodeling. PTSD patients have higher blood pressure both at rest and in response to stimuli. Although stress is associated with cardiovascular disease, the exact mechanism linking the two is still unknown. METHODS/STUDY POPULATION: Adult C57BL/6 mice underwent a PTSD induction protocol consisting of inescapable foot shock followed by single prolonged stress. The mice were assessed incrementally for their PTSD-like phenotype using specific behavioral tests chosen to assess for each of the human criteria of PTSD according to the DSM-V. Tail cuff blood pressure measurements were taken serially throughout the 16-week protocol. At terminal study, thoracic aortic diameter measurements were obtained through digital microscopy and plasma was harvested for cytokine analysis. Thoracic aortic aneurysms (TAA) were induced through periadventitial application of a calcium chloride solution on the descending thoracic aorta in BPH/2J and BPN/3J adult mice. The thoracic aortic diameter was measured at terminal study through digital microscopy. RESULTS/ANTICIPATED RESULTS: Using our PTSD-like mouse model we have demonstrated that PTSD-like mice have significantly higher systolic blood pressure following a reminder of the traumatic event than control mice recapitulating the human phenotype. They also had increased plasma proinflammatory cytokines and larger thoracic aortic diameters than control mice. Although the increased thoracic aortic diameter is not an aneurysm, it suggests ECM remodeling is occurring predisposing the aorta to aneurysm formation. Finally, we have shown that in neurogenic hypertensive mice, TAA formation was accelerated by 12 weeks with roughly 70% dilation at 4 weeks post-TAA induction surgery as compared to roughly a 20% dilation in control mice. DISCUSSION/SIGNIFICANCE: Altogether, these studies reinforce the link between stress and TAA development, and our mouse model will allow for the underlying mechanism to be elucidated. Better understanding of the mechanism linking PTSD and TAA will allow for the creation of novel therapeutics to treat PTSD symptoms while also delaying TAA progression.
6 - The Role of Metastasis Suppressor Genes in Metastasis
- from GENES
-
- By Brunilde Gril, National Cancer Institute, United States, Russell Szmulewitz, The University of Chicago, Committee on Cancer Biology and Pritzker School of Medicine, United States, Joshua Collins, National Cancer Institute, United States, Jennifer Taylor, The University of Chicago, Committee on Cancer Biology and Pritzker School of Medicine, United States, Carrie Rinker-Schaeffer, The University of Chicago, Committee on Cancer Biology and Pritzker School of Medicine, United States, Patricia Steeg, National Cancer Institute, United States, Jean-Claude Marshall, National Cancer Institute, United States
- Edited by David Lyden, Danny R. Welch, Bethan Psaila
-
- Book:
- Cancer Metastasis
- Published online:
- 05 June 2012
- Print publication:
- 25 April 2011, pp 64-76
-
- Chapter
- Export citation
-
Summary
In the 1970s and 1980s, clever scientific insight and innovation rapidly advanced our understanding of the molecular mechanisms of cancer biology. The discoveries of oncogenes and tumor suppressors, and the elucidation of their functions, greatly aided in studies aimed at a molecular understanding of the etiology of primary tumors. Despite this, cancer biologists had little understanding of the molecular aspects of metastasis. Considering the devastating consequences, scientists were anxious for a breakthrough. The first clue would come from the study of tumor suppressors.
Tumor suppressor genes were identified when it was discovered that their loss of function was critical to tumorigenesis. Prior to their discovery, researchers were of the mindset that the oncogenic phenotype was always dominant. In other words, a mutation need happen on only a single allele for a normal cell to be transformed into a tumor cell. However, not all disease incidence data seemed to fit neatly into this hypothesis. By studying retinoblastoma case histories, a “two-hit” hypothesis emerged, predicting that for at least some cancers, two mutations must occur (one on each allele) to successfully transform a cell [1]. Indeed, the retinoblastoma gene, or Rb, would become known as the first described tumor suppressor. We now know that the “two hits” need not come in the form of distinct somatic mutations but may be the result of any combination of germinal and/or somatic mutations, mitotic recombinations, gene conversions, and functional inactivation of genes owing to promoter hypermethylation.