This is a pre-doctoral fellowship application to support an MD/PhD candidate's training to become a physician-scientist dedicated to the study and treatment of neurological disorders. Cerebral cavernous malformations (CCMs) are thin-walled, dilated, vascular lesions that occur primarily in the brain and spinal cord, causing a variety of neurological symptoms and stroke. CCM disease is caused by loss of function mutations in three non-homologous adaptor proteins: CCM1 (KRIT1), CCM2 (OSM), and CCM3 (PDCD10), forming a heterotrimeric ?CCM complex?. Evidence from mouse and patient studies strongly suggest that the CCM complex is specifically required in endothelial cells to prevent disease. This complex interacts with MEKK3 (MAP3K3) through direct binding between CCM2 and MEKK3. We have demonstrated, in a mouse model of CCM disease, that the CCM complex negatively regulates MEKK3 signaling in endothelial cells. In the disease state, disruption of the CCM complex results in gain of MEKK3 signaling and pathologic over-expression of KLF2 and KLF4 (KLF2/4) transcription factors. From genetic rescue experiments in mice and corroborating human disease studies, it is clear that this endothelial MEKK3?KLF2/4 pathway is required for the development of CCMs. The proposed studies will investigate downstream and upstream pathways of MEKK3?KLF2/4 signaling in the context of CCM disease with the overarching goal of identifying translational opportunities for the benefit of patients.
In Aim 1, we will test the hypothesis that CCMs arise from the KLF2/4- driven, over-secretion of ADAMTS metalloproteases that undermine the extracellular matrix of the vasculature. This will be done using genetic rescue and sufficiency strategies in the CCM disease mouse model. Previous studies have shown Toll-like receptor 4 (TLR4) signaling to activate the MEKK3 pathway. Moreover, TLR4 polymorphisms are strongly associated with CCM disease severity in humans.
In Aim 2, we will investigate the role of endothelial Toll-like receptor 4 (TLR4) signaling in CCM disease using pharmacologic and genetic manipulation of the CCM disease mouse model.

Public Health Relevance

Cerebral cavernous malformations (CCMs) are thin-walled, vascular lesions occurring primarily in the brain and spinal cord, with a prevalence of nearly 1% in the general population. CCMs arise from the pathologic gain of MEKK3 signaling, a MAP-3kinase specifically required in endothelial cells to maintain vascular integrity. Proposed studies will investigate the role of upstream and downstream MEKK3 signaling pathways in the context of CCM disease to identify therapeutically-viable molecular targets for a disease where the only treatment option remains invasive neurosurgery.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
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Neurological Sciences Training Initial Review Group (NST)
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Koenig, James I
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University of Pennsylvania
Schools of Medicine
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Zeineddine, Hussein A; Girard, Romuald; Saadat, Laleh et al. (2018) Phenotypic characterization of murine models of cerebral cavernous malformations. Lab Invest :
Tang, Alan T; Choi, Jaesung P; Kotzin, Jonathan J et al. (2017) Endothelial TLR4 and the microbiome drive cerebral cavernous malformations. Nature 545:305-310