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Identifying the subcellular compartment(s) that serves as the major signaling platform for PDGFR homodimers and heterodimers

Award Number: F31DE036451
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Identifying the subcellular compartment(s) that serves as the major signaling platform for PDGFR homodimers and heterodimers - Project Summary Craniofacial development is a dynamic morphogenetic process. Any disruption to this process can cause the developing organism to suffer from a range of highly prevalent complications. Platelet-derived growth factor receptors (PDGFRs) play important roles in vertebrate craniofacial development. Human PDGFRA variants are associated with non-syndromic cleft/lip palate, while PDGFRB variants cause syndromes characterized by craniofacial dysmorphism. PDGFR signaling has been shown to be essential for cranial neural crest cell migration, and proliferation and survival of the craniofacial mesenchyme. There are two members of the PDGFR family, PDGFR and PDGFR, which can homodimerize or heterodimerize in response to ligand binding, unleashing an intracellular signaling cascade. Previous research on PDGFRs has been limited by an inability to study dimer-specific dynamics. Using a novel bimolecular fluorescence complementation (BiFC) approach, the Fantauzzo laboratory was able to visualize and purify individual PDGFR dimers both in vitro and in vivo, revealing differences in the timing and extent of dimer activation, internalization, trafficking, and downstream signaling, which translated into differences in cell migration and proliferation. However, it is still unclear whether PDGFR internalization and trafficking into different subcellular compartments is required to propagate a downstream intracellular signaling response, particularly in craniofacial-relevant models. The goals of this study are to identify the subcellular compartment(s) that serves as the major signaling platform for each PDGFR dimer and to explore how mistrafficking of these receptors affects downstream intracellular signaling. First, the effects of inhibiting clathrin-mediated internalization on PDGFR signaling will be examined biochemically using immortalized mouse embryonic palatal mesenchyme (MEPM) cell lines derived from novel PDGFR-BiFC mouse models. Next, the subcellular compartment(s) in which the various PDGFR dimers propagate a signal will be identified via subcellular fractionation. Moreover, the effects of disrupting trafficking through various endosomal compartments on PDGFR signaling will be examined using dominant-negative Rab proteins. Second, the effects of two craniofacial disease-associated variants on PDGFR trafficking will be examined in HCC15 cancer cells and eventually PDGFR-BiFC MEPM cells via expression and biochemical assays. These studies will explore a link between PDGFR dimer trafficking and downstream signaling to provide insight into the mechanisms underlying craniofacial development, which may lead to improved treatment for patients affected by variants in genes encoding receptor tyrosine kinases and associated signaling molecules. The research training plan includes techniques from the fields of genetics, developmental biology and biochemistry. Mentorship will be provided by Dr. Katherine Fantauzzo (Sponsor). The career development training plan will provide opportunities for increased knowledge of cellular signaling and craniofacial development, confidence in public speaking, proficiency in scientific writing, networking and mentoring.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $43,880 )
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	001	1	9/1/2026	NEW	$0
2026	2026	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Oral Diseases and Disorders Research	000	1	9/1/2026	NEW	$43,880
														Subtotal = $43,880

Grand Total All Awards = $43,880

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Identifying the subcellular compartment(s) that serves as the major signaling platform for PDGFR homodimers and heterodimers

Award Number: F31DE036451

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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