# Regulation of endothelial gene expression by cerebral cavernous malformation complex

> **NIH NIH K01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2022 · $180,684

## Abstract

Project Summary/Abstract
The Mentored Career Development Award will give me the opportunity to receive the additional training
and research experience necessary to achieve my long-term goal of obtaining an independent faculty
position at a research-oriented university, and contribute to the field of Cardiovascular Biology. The
proposed project is a valuable tool to extent my knowledge and expertise in complex research
methods, including mouse and zebrafish genetics/molecular biology, that are applied in the
cardiovascular field. The University of California, San Diego (UCSD) School of Medicine conducts
research in a multidisciplinary and highly collaborative environment by interacting with colleagues that
span clinical medicine to structural and molecular biology. Moreover, the Ginsberg laboratory is well
equipped with cellular, proteomic, and molecular biology tools to understand cellular and molecular
biology of the protein products of genes implicated in cerebral cavernous malformations (CCM) (KRIT1,
Krev- Interaction Trapped-1, CCM2, and PDCD10). In order to identify the major molecular processes
involved in loss of Krit1-induced altered endothelial phenotype and function, a cell culture model to
delete Krit1 in mouse endothelium in a time-controlled manner was established. To this end, transgenic
mice bearing floxed alleles of Krit1 (Krit1fl/fl) and an endothelial-specific tamoxifen-regulated Cre
recombinase (Pdgfb-iCreERT2) were used. In preliminary studies, an increase in expression of
Kruppel-like factor 2 (KLF2), a transcription factor implicated in the effects of Krit1 on zebrafish heart
development, and a decrease in expression of Thrombospondin 1(TSP1), an anti-angiogenic protein
that antagonizes VEGF signaling, was observed. Gain-of-function experiments will be performed to
assess whether re-expression of TSP1 can reverse loss of KRIT1 affects endothelial phenotype and
function. Moreover, this will be extended by investigating whether TSP1 gene transcription is
suppressed as a consequence of deletion of Krit1 in cultured cells. Since SP1/KLF binding sites in
human and mouse TSP1 promoter region were identified, the role of KLF2 in downregulation of TSP1
in response to genetic inactivation of Krit1 will be investigated. In addition, the zebrafish CCM model
will be used to assess the impact of loss of Tsp1 during cardiovascular malformations in vivo. The
studies described in this proposal and the environment at UCSD will complete my training in complex
research methods and provide insight into fundamental questions about the function of the KRIT1 gene
at the endothelial cell and organism level.

## Key facts

- **NIH application ID:** 10430055
- **Project number:** 5K01HL133530-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Miguel Alejandro Lopez-Ramirez
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $180,684
- **Award type:** 5
- **Project period:** 2018-05-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10430055

## Citation

> US National Institutes of Health, RePORTER application 10430055, Regulation of endothelial gene expression by cerebral cavernous malformation complex (5K01HL133530-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10430055. Licensed CC0.

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