Browsing by Author "Hoffmann-Longtin, Krista J."

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    The Role of Heme Synthesis in Endothelial Mitochondrial Function and Ocular Angiogenesis
    (2020-08) Shetty, Trupti; Corson, Timothy W.; Bhatwadekar, Ashay D.; Hoffmann-Longtin, Krista J.; Jerde, Travis J.; Lu, Tao; Sullivan, William J., Jr.
    Abnormal blood vessel growth from pre-existing blood vessels, termed pathological angiogenesis, is a common characteristic of vascular diseases like proliferative diabetic retinopathy (PDR) and wet age-related macular degeneration (wet AMD). Retinal detachment, hemorrhage, and loss of vision are only some of the debilitating consequences of advanced pathological angiogenesis. Current therapeutics targeting these blood vessels are ineffective in many patients. We previously identified a novel angiogenesis target, ferrochelatase (FECH), from the heme synthesis pathway, and found that FECH inhibition is antiangiogenic in cell and animal models. Heme synthesis occurs in mitochondria, where FECH inserts Fe2+ into protoporphyrin IX (PPIX) to produce heme. However, the relationship between heme metabolism and angiogenesis is poorly understood. I sought to understand the mechanism of how FECH and thus, heme is involved in endothelial cell function. First, I determined the energetic state of retinal and choroidal endothelial cells, previously uncharacterized. I found that mitochondria in endothelial cells had several functional defects after heme inhibition. FECH loss changed the shape of mitochondria and depleted expression of genes maintaining mitochondrial dynamics. FECH blockade elevated oxidative stress and depolarized mitochondrial membrane potential. Heme depletion had negative effects on cellular metabolism, affecting oxidative phosphorylation and glycolysis. Mitochondrial complex IV of the electron transport chain (cytochrome c oxidase) was decreased in cultured human retinal endothelial cells and in murine retina ex vivo after FECH inhibition. Supplementation with heme partially rescued phenotypes of FECH blockade. Additionally, I discovered that partial loss-of-function Fech mutation in mice caused PPIX accumulation with no change in normal vasculature, as assessed by fundoscopy. These findings provide an unexpected link between mitochondrial heme metabolism and angiogenesis. My studies identify a novel role of a heme synthesis enzyme in blood vessel formation and provide an opportunity to exploit these findings therapeutically for patients with PDR and wet AMD.
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    Stepping Stones: Nine Lessons from Women Leaders in Academic Medicine
    (Texas A&M University, 2013) Palmer, Megan M.; Hoffmann-Longtin, Krista J.; Walvoord, Emily C.; Dankoski, Mary E.
    Women now make up half of all medical school matriculates; yet few women hold leadership positions in academic health centers. The reasons for this gender gap are complex and have been the subject of much discussion. However, the experiences of women who successfully ascend to positions of senior leadership are rarely examined. It is critical to develop a greater understanding of women's paths to leadership positions in order to inspire and enable more women to seek such opportunities. Using a semi-structured protocol, we interviewed 16 women leaders who were willing to share their career journeys in a public forum. These leaders were asked to share pivotal moments or milestones, referred to as "stepping stones," in their careers. The interviews were taped, transcribed and analysed for significant patterns and consistent themes. Nine themes were identified and included: hold fast to your values; be open to unexpected opportunities; surround yourself with people who believe in you and people you believe in; be assertive in your communication and actions; continually refine your leadership skills; don't take things personally; stay organized; build positive relationships and welcoming environments; and when and if necessary, prove them wrong. The women leaders had strikingly similar lessons to share. This study develops a deeper understanding of the career paths of women in leadership positions, setting the stage for future study as well as encouraging and empowering more women to climb the leadership ladder.