# Signal transduction in development and disease

> **NIH NIH R35** · STANFORD UNIVERSITY · 2024 · $737,779

## Abstract

Project Summary
Signal transduction in development and disease (PI: Rohatgi)
The goals of my research program are to uncover new regulatory mechanisms in cell-cell communication
pathways, to understand how these mechanisms are damaged in disease states, and to devise new strategies
to repair their function. Over the last 4.5 years, funding from the NIGMS has supported 23 publications across
four different research areas in my laboratory: Hedgehog (Hh) signaling, WNT signaling, drug resistance
mechanisms and intrinsically disordered proteins. Trainees involved in MIRA-supported research have won
competitive fellowships (including a K99/R00 award from the NIGMS) and obtained independent group leader
positions in both academia and industry. The next project period will tackle major unsolved problems in the
vertebrate Hh and WNT signaling systems, two iconic cell-cell communication pathways that coordinate the
construction of tissues during development and their subsequent maintenance throughout adult life. Despite the
importance of these pathways in human diseases ranging from birth defects to cancer and degenerative
conditions, many steps in Hh and WNT signaling remain poorly understood at the biochemical and cell biological
level. In the Hh pathway, our focus is on understanding how a signal is detected at the cell surface and
transmitted across the plasma membrane to transcriptional effectors in the cytoplasm. These signaling steps in
the vertebrate Hh pathway depend on primary cilia, antenna-like organelles that project from the surfaces of
most cells and are implicated in human birth defect syndromes called “ciliopathies.” Major questions under
investigation include (1) how Patched 1 (PTCH1), the receptor for Hh ligands, regulates the function of
Smoothened (SMO), the protein that transmits the signal across the membrane, (2) how SMO is activated at
primary cilia and (3) how SMO signals to the Glioblastoma (GLI) family of transcription factors. Our MIRA-
supported work has led to a new paradigm in transmembrane signaling: the use of cholesterol accessibility in
the ciliary membrane as a second messenger to communicate the signal between PTCH1 and SMO. Our focus
in the WNT pathway is on the multi-protein β-catenin destruction complex that suppresses WNT signaling by
promoting the degradation of β-catenin. Defects in this complex drive the vast majority of colorectal cancer, a
disease with an increasing burden (especially amongst people <50 years of age) predicted to cause over 1
million deaths yearly by 2030. Our emphasis is on uncovering differences in the genetic and biochemical
requirements for oncogenic (mutation-driven) and physiological (ligand-driven) WNT signaling, since any
successful anti-WNT drug will have to distinguish between the two to achieve an acceptable therapeutic index.
Our work is supported by long-term collaborations and embraces a broad range of techniques that span structural
biology, lipid biochemistry, CRISPR/Cas9-base...

## Key facts

- **NIH application ID:** 10872166
- **Project number:** 5R35GM118082-09
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** RAJAT ROHATGI
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $737,779
- **Award type:** 5
- **Project period:** 2016-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10872166

## Citation

> US National Institutes of Health, RePORTER application 10872166, Signal transduction in development and disease (5R35GM118082-09). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10872166. Licensed CC0.

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