Matthew McCarra

All Publications

• WNT7A deficit is associated with dysfunctional angiogenesis in pulmonary arterial hypertension. The European respiratory journal Chakraborty, A., Nathan, A., Orcholski, M., Agarwal, S., Shamskhou, E. A., Auer, N., Mitra, A., Guardado, E. S., Swaminathan, G., Condon, D. F., Yu, J., McCarra, M., Juul, N. H., Mallory, A., Guzman-Hernandez, R. A., Yuan, K., Rojas, V., Crossno, J. T., Yung, L., Yu, P. B., Spencer, T., Winn, R. A., Frump, A., Karoor, V., Lahm, T., Hedlin, H., Fineman, J. R., Lafyatis, R., Knutsen, C. N., Alvira, C. M., Cornfield, D. N., de Jesus Perez, V. A. 2023

  Abstract

  INTRODUCTION: Pulmonary arterial hypertension (PAH) is characterized by loss of microvessels. The Wnt pathways control pulmonary angiogenesis, but their role in PAH is incompletely understood. We hypothesized that Wnt activation in pulmonary microvascular endothelial cells (PMVECs) is required for pulmonary angiogenesis, and its loss contributes to PAH.METHODS: Lung tissue and PMVECs from healthy and PAH patients were screened for Wnt production. Global and endothelial-specific Wnt7a-/- mice were generated and exposed to chronic hypoxia and Sugen-hypoxia (SuHx).RESULTS: Healthy PMVECs demonstrated >6-fold Wnt7a expression during angiogenesis that was absent in PAH PMVECs and lungs. Wnt7a expression correlated with formation of tip cells, a migratory endothelial phenotype critical for angiogenesis. PAH PMVECs demonstrated reduced VEGF-induced tip cell formation as evidenced by reduced filopodia formation and motility, which was partially rescued by recombinant Wnt7a. We discovered that Wnt7a promotes VEGF signaling by facilitating Y1175 tyrosine phosphorylation in VEGFR2 through ROR2, a Wnt-specific receptor. We found that ROR2 knockdown mimics Wnt7a insufficiency and prevents recovery of tip cell formation with Wnt7a stimulation. While there was no difference between wild-type and endothelial-specific Wnt7a-/- mice under either chronic hypoxia and SuHx, global Wnt7a+/- mice in hypoxia demonstrated higher pulmonary pressures and severe right ventricular and lung vascular remodeling. Similar to PAH, Wnt7a+/- PMVECs exhibited insufficient angiogenic response to VEGF-A that improved with Wnt7a.CONCLUSIONS: Wnt7a promotes VEGF signaling in lung PMVECs and its loss is associated with insufficient VEGF-A angiogenic response. We propose that Wnt7a deficiency contributes to progressive small vessel loss in PAH.

  View details for DOI 10.1183/13993003.01625-2022

  View details for PubMedID 37024132

• First lung and kidney multi-organ transplant following COVID-19 Infection. The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation Guenthart, B. A., Krishnan, A., Alassar, A., Madhok, J., Kakol, M., Miller, S., Cole, S. P., Rao, V. K., Acero, N. M., Hill, C. C., Cheung, C., Jackson, E. C., Feinstein, I., Tsai, A. H., Mooney, J. J., Pham, T., Elliott, I. A., Liou, D. Z., La Francesca, S., Shudo, Y., Hiesinger, W., MacArthur, J. W., Brar, N., Berry, G. J., McCarra, M. B., Desai, T. J., Dhillon, G. S., Woo, Y. J. 2021

  Abstract

  As the world responds to the global crisis of the COVID-19 pandemic an increasing number of patients are experiencing increased morbidity as a result of multi-organ involvement. Of these, a small proportion will progress to end-stage lung disease, become dialysis dependent, or both. Herein, we describe the first reported case of a successful combined lung and kidney transplantation in a patient with COVID-19. Lung transplantation, isolated or combined with other organs, is feasible and should be considered for select patients impacted by this deadly disease.

  View details for DOI 10.1016/j.healun.2021.02.015

  View details for PubMedID 34059432

• Lung stem cells and therapy for cystic fibrosis Lung Stem Cells in Development, Health and Disease Vaidyanathan, S., McCarra, M. B., Desai, T. European Respiratory Society. 2021; 91: 06-321

  View details for DOI 10.1183/2312508X.10010520

• Obstructive sleep apnea: can the downward spiral be reversed-a summary of John Stradling's ATS keynote speech. Journal of thoracic disease McCarra, M. B., Owens, R. L. 2016; 8 (Suppl 7): S539-41

  View details for DOI 10.21037/jtd.2016.07.26

  View details for PubMedID 27606087

  View details for PubMedCentralID PMC4990690

• Development of clinical immunity to malaria in highland areas of low and unstable transmission. The American journal of tropical medicine and hygiene Rolfes, M. A., McCarra, M., Magak, N. G., Ernst, K. C., Dent, A. E., Lindblade, K. A., John, C. C. 2012; 87 (5): 806-12

  Abstract

  In highland areas of unstable, low malaria transmission, the extent to which immunity to uncomplicated malaria develops with age and intermittent parasite exposure has not been well characterized. We conducted active surveillance for clinical malaria during April 2003-March 2005 in two highland areas of western Kenya (Kapsisiywa and Kipsamoite). In both sites, annual malaria incidence was significantly lower in persons ≥ 15 years of age than in persons < 5 years of age (Kapsisiywa: incidence = 382.9 cases/1,000 persons among persons < 1-4 years of age versus 135.1 cases/1,000 persons among persons ≥ 15 years of age; Kipsamoite: incidence = 233.0 cases/1,000 persons in persons < 1-4 years of age versus 43.3 cases/1,000 persons in persons ≥ 15 years of age). In Kapsisiywa, among persons with malaria, parasite density and axillary body temperature were also significantly lower in persons ≥ 15 years of age than in persons < 5 years of age. Even in highland areas of unstable and low malaria transmission, age is associated with development of clinical immunity to malaria.

  View details for DOI 10.4269/ajtmh.2012.11-0530

  View details for PubMedID 22987652

  View details for PubMedCentralID PMC3516254

• Antibodies to Plasmodium falciparum erythrocyte-binding antigen-175 are associated with protection from clinical malaria. The Pediatric infectious disease journal McCarra, M. B., Ayodo, G., Sumba, P. O., Kazura, J. W., Moormann, A. M., Narum, D. L., John, C. C. 2011; 30 (12): 1037-42

  Abstract

  Antibodies to blood-stage Plasmodium falciparum antigens have been associated with protection against clinical malaria in some studies but not others. Many of these studies have not assessed whether high-titer antibodies are associated with protection and have not adjusted for differences in malaria exposure.The presence of high-titer antibodies to apical membrane antigen-1, erythrocyte-binding antigen-175 (EBA-175), and merozoite surface protein-1₁₉ (MSP-1₁₉) was assessed in 87 children living in a malaria holoendemic area of Kenya. The children were prospectively assessed during 1 year for clinical malaria.In unadjusted analyses, high-titer antibodies to MSP-1₁₉, but not EBA-175 or apical membrane antigen-1, were associated with protection from clinical malaria. However, after adjustment for exposure, only high-titer antibodies to EBA-175 were associated with protection from clinical malaria (hazard ratio, 0.48; 95% confidence interval [CI], 0.24, 0.95; P = 0.03), and with reduced episodes of clinical malaria (incidence rate ratio, 0.50; 95% CI, 0.31, 0.81; P = 0.005). A trend toward increased protection from clinical malaria in children was seen with antibodies to both EBA-175 and MSP-1₁₉ (hazard ratio, 0.26; 95% CI, 0.03, 1.94; P = 0.18).High-titer antibodies to EBA-175 are associated with protection from clinical malaria in children in a malaria holoendemic area of Kenya. Accurate estimates of antibody-associated protection from clinical malaria require adjustment for malaria exposure.

  View details for DOI 10.1097/INF.0b013e31822d1451

  View details for PubMedID 21817955

  View details for PubMedCentralID PMC3222715

• Infant hearing loss and connexin testing in a diverse population. Genetics in medicine : official journal of the American College of Medical Genetics Schimmenti, L. A., Martinez, A., Telatar, M., Lai, C. H., Shapiro, N., Fox, M., Warman, B., McCarra, M., Crandall, B., Sininger, Y., Grody, W. W., Palmer, C. G. 2008; 10 (7): 517-24

  Abstract

  Previous studies of connexin-related hearing loss have typically reported on mixed age groups or adults. To further address epidemiology and natural history of connexin-related hearing loss, we conducted a longitudinal study in an ethnically diverse cohort of infants and toddlers under 3 years of age. Our study compares infants with and without connexin-related hearing loss to examine differences in the prevalence of connexin and non-connexin-related hearing loss by ethnic origin, detection by newborn hearing screening, phenotype, neonatal risk factors, and family history. This is the first study to differentiate infants with and without connexin-related hearing loss.We enrolled 95 infants with hearing loss from whom both exons of Cx26 were sequenced and the Cx30 deletion was assayed. Demographic, family history, newborn hearing screening data, perinatal, and audiologic records were analyzed.Genetic testing identified biallelic Cx26/30 hearing loss-associated variants in 24.7% of infants with a significantly lower prevalence in Hispanic infants (9.1%). Eighty-two infants underwent newborn hearing screening; 12 infants passed, 3 had connexin-related hearing loss. No differences in newborn hearing screening pass rate, neonatal complications, or hearing loss severity were detected between infants with and without connexin-related hearing loss. Family history correlates with connexin-related hearing loss.Connexin-related hearing loss occurs in one quarter of infants in an ethnically diverse hearing loss population but with a lower prevalence in Hispanic infants. Not all infants with connexin-related hearing loss fail newborn hearing screening. Family history correlates significantly with connexin-related hearing loss. Genetic testing should not be deferred because of newborn complications. These results will have an impact on genetic testing for infant hearing loss.

  View details for DOI 10.1097/gim.0b013e31817708fa

  View details for PubMedID 18580690