# Notch/Robo Regulated Mechanisms Governing Cell Fate Acquisition

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA SANTA CRUZ · 2021 · $527,930

## Abstract

Program Director/Principal Investigator (Hinck, Lindsay, E.):
There is a fundamental gap in understanding the role of tissue specific stem/progenitor cells and their capacity
for division and renewal. In tissues such as the breast, these cells undergo expansive growth and
differentiation with every pregnancy. Yet, mechanisms regulating the generation of binucleated, milk-producing
alveolar cells are scarcely understood. Until this knowledge gap is closed, we will be unable to support the
substantial number of women who produce insufficient milk. The long-term goal of this research is to
understand how mammals harness stem/progenitor cells to build a milk supply. Recently, it was discovered
that a large fraction of cells become polyploid during mammary alveologenesis, a process required for milk
production. This proposal's objective is to identify the signaling pathways regulating the generation of polyploid
cells via endoreplication in response to DNA damage generated by replication stress, and determine the
impact of these pathways on milk production. The central hypothesis is that ROBO-regulated NOTCH signaling
governs the DNA damage differentiation response and endoreplication that occurs in response to alveolar
progenitor cell expansion and differentiation. Our hypothesis is based on our own preliminary data that ROBOs
differentially regulate alveologenesis and Notch signaling, and that, together, Robo/Notch signaling regulates
the response to DNA damage, which we find occurring during alveologenesis. The rationale underlying this
proposal is that the identification of these pathways will allow for interventions, pharmacological or dietary, that
improve alveolar development and milk production. Guided by strong preliminary data, three hypotheses will
be tested in three Aims: 1) ROBO1 promotes differentiation by restricting the activation of one or more NOTCH
receptors in AVPs. 2) ROBO2 inhibits differentiation by activating the signaling of one or more Notch receptors
either directly or by acting through ROBO1. 3) Replication stress, occurring during the expansion phase of
pregnancy, is the source of DNA damage, triggering the DNA damage differentiation response and
endoreplication that is governed by Robo/Notch signaling. The proposed research is significant because it will
identify new methods for increasing milk production. The proposed research is innovative because we propose
that harnessing stem/progenitor cells can enhance milk production. Previous studies have focused on the
prolactin pathway and only yielded drugs with significant negative side effects. The proposed research will
have a positive impact for women who produce insufficient milk and their children who do not reap the benefits
of this “liquid gold”.
PHS 398 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page

## Key facts

- **NIH application ID:** 10134860
- **Project number:** 5R01HD098722-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA CRUZ
- **Principal Investigator:** LINDSAY E HINCK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $527,930
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10134860

## Citation

> US National Institutes of Health, RePORTER application 10134860, Notch/Robo Regulated Mechanisms Governing Cell Fate Acquisition (5R01HD098722-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10134860. Licensed CC0.

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