# Competition and morphogenesis in tip cell-mediated branching of tubular networks

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $335,807

## Abstract

Ghabrial – Project Summary
To build a functional vascular system, a network of endothelial tubes must be generated through a combination
of vasculogenesis and angiogenesis. During sprouting angiogenesis, endothelial tip cells lead the outgrowth of
new branches. Tip cells anastomose with other tip cells or with pre-existing tubes. At the same time, tip cells
must also lumenize so that the tubes become patent. Studies in zebrafish indicate tip cells lumenize by a
process that an intracellular tube that, in cross section, lacks junctional seams (seamless tube). Even tip cells
that later remodel to contribute to multicellular tubes, pass through a seamless tube intermediate stage.
Likewise, during primary branching of the Drosophila respiratory system, tracheal tip cells lead the outgrowth of
new branches. To form a network, some tracheal tip cells anastomose (fusion cells) while others (terminal
cells) branch extensively to produce dozens of blind ended tubes that ramify on target tissues and act as the
sites of gas exchange. Like endothelial tip cells, tracheal tip cells form seamless tubes. Cell biological studies
have led to the current model of seamless tube formation by inverse membrane blebbing; however, very little is
known about the genetic and molecular pathways that are required. We have been exploiting the powerful
forward genetic approaches possible in Drosophila to meet our long-term objective of pioneering an
understanding of the genetic and molecular framework required to make, shape and maintain seamless tubes.
The rationale of our approach is that the fundamental rules and genetic pathways operative in Drosophila are
likely to be conserved throughout the animal kingdom. As we build our understanding by identifying novel
genes required for seamless tube morphogenesis (AIM 1: Determine the molecular identity and function of
the cystic lumens gene.), we also go deeper – using molecular genetic, cellular, and proteomic approaches –
to identify additional components and mechanisms of action for genetic pathways we have previously
identified, and extending our findings to endothelial seamless tubes (AIM 2: Elucidate the cellular and
molecular mechanisms of TBC1D10 and Rab35 action in seamless tube growth). Additionally, one
seamless tubulogenesis pathway (the Cerebral Cavernous Malformations 3-Germinal Center Kinase III
pathway) we identified, is known to be critical in endothelial cells, as mutations in orthologous human genes
lead to familial vascular disease. Using Drosophila genetic and proteomic approaches, we have identified
factors required both upstream and downstream in the CCM3-GCKIII pathway, and now propose to more
clearly define the biological consequences of perturbing the pathway and to identify the downstream targets of
the signaling pathway. Given the conserved role of CCM3 in tubulogenesis, we also seek to extend our results
to the vertebrate endothelial system, making use of zebrafish, whose unique properties will allow...

## Key facts

- **NIH application ID:** 9991854
- **Project number:** 5R01GM089782-11
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** AMIN S GHABRIAL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,807
- **Award type:** 5
- **Project period:** 2010-07-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9991854

## Citation

> US National Institutes of Health, RePORTER application 9991854, Competition and morphogenesis in tip cell-mediated branching of tubular networks (5R01GM089782-11). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9991854. Licensed CC0.

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