{"id":6072,"date":"2024-06-07T10:33:42","date_gmt":"2024-06-07T14:33:42","guid":{"rendered":"https:\/\/www.med.unc.edu\/bloodresearchcenter\/?p=6072"},"modified":"2024-07-01T10:11:40","modified_gmt":"2024-07-01T14:11:40","slug":"alisa-wolberg-and-karin-leiderman-awarded-mpi-nih-r01-grant","status":"publish","type":"post","link":"https:\/\/www.med.unc.edu\/bloodresearchcenter\/2024\/06\/alisa-wolberg-and-karin-leiderman-awarded-mpi-nih-r01-grant\/","title":{"rendered":"Alisa Wolberg and Karin Leiderman awarded MPI NIH R01 Grant"},"content":{"rendered":"<p>A new MPI NIH R01 was awarded to Alisa Wolberg, PhD and Karin Leiderman, PhD of University of North Carolina at Chapel Hill School of Medicine, entitled: \u201cInterdisciplinary Approach to Elucidate Modifiers of Bleeding Phenotype in Factor XI Deficiency.\u201d<\/p>\n<p>PROJECT SUMMARY Congenital\u00a0<em>deficiency<\/em>\u00a0of plasma clotting\u00a0<em>factor<\/em>\u00a0(F)<em>XI<\/em>\u00a0is an autosomal disorder. Whereas some individuals are asymptomatic (non-bleeders), others have excessive\u00a0<em>bleeding<\/em>\u00a0after injury, primarily at sites with high fibrinolytic activity (mouth, nose, genitourinary tract) (bleeders). People with similarly reduced F<em>XI<\/em>\u00a0have variable\u00a0<em>bleeding<\/em>\u00a0even within families sharing the same F<em>XI<\/em>\u00a0mutation. Clinical assays cannot predict\u00a0<em>bleeding<\/em>\u00a0risk in F<em>XI<\/em>-deficient people, leading to under- or over-treatment to prevent bleeds. Moreover, F<em>XI<\/em>\u00a0inhibition strategies are in clinical trials to reduce thrombosis; however, observations of individuals with congenital F<em>XI<\/em>\u00a0<em>deficiency<\/em>\u00a0suggest these therapies will incur\u00a0<em>bleeding<\/em>\u00a0risk in some patients, especially in prophylactic use. Uncovering mechanisms that determine\u00a0<em>bleeding<\/em>\u00a0risk in F<em>XI<\/em>\u00a0<em>deficiency<\/em>\u00a0and developing methods to predict\u00a0<em>bleeding<\/em>\u00a0will improve treatment for both\u00a0<em>bleeding<\/em>\u00a0and thrombosis. Our long-term goals are to characterize mechanisms that promote hemostasis in F<em>XI<\/em>\u00a0<em>deficiency<\/em>, and translate these findings into clinically-accessible methods to predict\u00a0<em>bleeding<\/em>. Using plasmas from two independent cohorts of well-<em>phenotype<\/em>d people with F<em>XI<\/em>\u00a0<em>deficiency<\/em>, we developed and validated specialized plasma assays that differentiate F<em>XI<\/em>-deficient bleeders from non-bleeders, and discovered that inhibiting the contact pathway in these assays enhances the ability to identify bleeders. We also integrated computational modeling and in vitro assays to uncover synergy between F<em>XI<\/em>a and tissue\u00a0<em>factor<\/em>\u00a0that enhances coagulation. We built on these discoveries with new analyses that revealed plasma proteins whose levels differed significantly between non-bleeders and bleeders, and a novel computational workflow for advancing a prediction model. These findings and advances provide important clues to mechanisms that modify\u00a0<em>bleeding<\/em>\u00a0risk in F<em>XI<\/em>\u00a0<em>deficiency<\/em>, and position us with innovative tools to identify these mechanisms. The objective of this application is to characterize the determinants and functional impact of differently present plasma proteins in non-bleeders and bleeders, and use computational methods to differentiate\u00a0<em>bleeding<\/em>\u00a0risk in F<em>XI<\/em>\u00a0<em>deficiency<\/em>. The central hypothesis of this application is that in F<em>XI<\/em>\u00a0<em>deficiency<\/em>, differences in plasma composition modify thrombin generation and clot formation, structure, and stability and determine the\u00a0<em>bleeding<\/em>\u00a0risk. Specific aims of this application are to: 1) Determine the functional impact and mechanisms differentiating differently present proteins in F<em>XI<\/em>-deficient non-bleeders and bleeders, 2) Use computational modeling and machine learning to identify predictive features that differentiate F<em>XI<\/em>-deficient non- bleeders and bleeders, and 3) Use multi-omic methods to define F<em>XI<\/em>\u00a0<em>deficiency<\/em>\u00a0and the\u00a0<em>bleeding<\/em>\u00a0<em>phenotype<\/em>. This proposed research is significant because the experiments will reveal molecular mechanisms that modify hemostatic potential in a predictive functional assay and in individuals with reduced F<em>XI<\/em>. Successful completion of this work will reveal new biology and lead to novel methods for predicting\u00a0<em>bleeding<\/em>\u00a0risk in individuals with congenital F<em>XI<\/em>\u00a0<em>deficiency<\/em>\u00a0and pharmacologically-reduced F<em>XI<\/em>\u00a0for thrombosis prevention.<\/p>\n<p>Read more on the grant here: <a href=\"https:\/\/grants.nih.gov\/grants\/funding\/r01.htm\">NIH Research Project Grant Program (R01) | grants.nih.gov<\/a><\/p>\n<p>Read more on the project: <a href=\"https:\/\/reporter.nih.gov\/search\/r27s7dhvs0Cb9a88EAUVZw\/project-details\/10900103\">RePORT \u27e9 RePORTER (nih.gov)<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"<p>A new MPI NIH R01 was awarded to Alisa Wolberg, PhD and Karin Leiderman, PhD of University of North Carolina at Chapel Hill School of Medicine, entitled: \u201cInterdisciplinary Approach to Elucidate Modifiers of Bleeding Phenotype in Factor XI Deficiency.\u201d PROJECT SUMMARY Congenital\u00a0deficiency\u00a0of plasma clotting\u00a0factor\u00a0(F)XI\u00a0is an autosomal disorder. Whereas some individuals are asymptomatic (non-bleeders), others have &hellip; <a href=\"https:\/\/www.med.unc.edu\/bloodresearchcenter\/2024\/06\/alisa-wolberg-and-karin-leiderman-awarded-mpi-nih-r01-grant\/\" aria-label=\"Read more about Alisa Wolberg and Karin Leiderman awarded MPI NIH R01 Grant\">Read more<\/a><\/p>\n","protected":false},"author":117184,"featured_media":6073,"comment_status":"closed","ping_status":"closed","sticky":false,"template":"","format":"standard","meta":{"_acf_changed":false,"layout":"","cellInformation":"","apiCallInformation":"","footnotes":"","_links_to":"","_links_to_target":""},"categories":[2],"tags":[],"class_list":["post-6072","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-news","odd"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v26.8 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Alisa Wolberg and Karin Leiderman awarded MPI NIH R01 Grant | UNC Blood Research Center<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.med.unc.edu\/bloodresearchcenter\/2024\/06\/alisa-wolberg-and-karin-leiderman-awarded-mpi-nih-r01-grant\/\" \/>\n<meta property=\"og:locale\" content=\"en_US\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Alisa Wolberg and Karin Leiderman awarded MPI NIH R01 Grant | UNC Blood Research Center\" \/>\n<meta property=\"og:description\" content=\"A new MPI NIH R01 was awarded to Alisa Wolberg, PhD and Karin Leiderman, PhD of University of North Carolina at Chapel Hill School of Medicine, entitled: \u201cInterdisciplinary Approach to Elucidate Modifiers of Bleeding Phenotype in Factor XI Deficiency.\u201d PROJECT SUMMARY Congenital\u00a0deficiency\u00a0of plasma clotting\u00a0factor\u00a0(F)XI\u00a0is an autosomal disorder. Whereas some individuals are asymptomatic (non-bleeders), others have &hellip; Read more\" \/>\n<meta property=\"og:url\" content=\"https:\/\/www.med.unc.edu\/bloodresearchcenter\/2024\/06\/alisa-wolberg-and-karin-leiderman-awarded-mpi-nih-r01-grant\/\" \/>\n<meta property=\"og:site_name\" content=\"UNC Blood Research Center\" \/>\n<meta property=\"article:published_time\" content=\"2024-06-07T14:33:42+00:00\" \/>\n<meta property=\"article:modified_time\" content=\"2024-07-01T14:11:40+00:00\" \/>\n<meta property=\"og:image\" content=\"https:\/\/www.med.unc.edu\/bloodresearchcenter\/wp-content\/uploads\/sites\/1089\/2024\/06\/WolbergAlisa2010.jpg\" \/>\n\t<meta property=\"og:image:width\" content=\"188\" \/>\n\t<meta property=\"og:image:height\" content=\"250\" \/>\n\t<meta property=\"og:image:type\" content=\"image\/jpeg\" \/>\n<meta name=\"author\" content=\"martimic\" \/>\n<meta name=\"twitter:card\" content=\"summary_large_image\" \/>\n<meta name=\"twitter:label1\" content=\"Written 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