Molecular basis for BMP receptor specialization and trafficking

Active Project Grant Awarded Last action

Award ID
F32HD114468
Recipient
Awarding agency
Obligated
$652,592

Award facts

Completion date 84% complete
Place of performance
Philadelphia, PA 19104, USA

Award details come from USAspending.gov.

Description

As the agency reported it.

Abstract
Bone morphogenetic protein (BMP) signaling, as part of the TGF-beta signaling family, is a major driver of developmental processes. Mutations in genes encoding BMP pathway components are associated with cardiovascular, pulmonary, and skeletal diseases as well as cancer. Developmentally, bmps serve as morphogens, with slight changes in signal level resulting in distinct cell fates. For instance, during dorsoventral axial patterning, the BMP gradient patterns the axial tissue with high BMP levels instructing ventral cell fates. Precise regulation of the BMP morphogen gradient is required for proper signaling and patterning, though has mostly focused on how ligand concentration and activity impact biological outcomes. Our lab has recently shown that during dorsoventral patterning, there are two required type i BMP receptors, ACVR1L and BMPR1A; however, only the kinase activity of ACVR1L is required for signaling. The specific requirement of BMPR1A has not been identified, nor have the distinct requirements for type II receptors. Prior work in other systems has also demonstrated that trafficking of TGF-beta receptors can attenuate or dampen signal transduction, representing another mechanism by which receptor activity can alter BMP signaling. Mutations in BMP receptors are associated with cancer and, specifically, mutations in ACVR1 are associated with brain gliomas and the developmental disorder fibrodysplasia ossificans progressiva, though how these mutations impact BMP signaling levels and lead to disease are still being defined. Here, i propose to determine the molecular basis for BMP receptor specialization and trafficking using zebrafish dorsoventral axial patterning as a model. I hypothesize that the BMP signaling gradient is interpreted by specialized receptor functions and trafficking to fine tune signal transduction downstream of ligand concentration. Building upon recent evidence that type i BMP receptors have specialized roles in the zebrafish gastrula, i will directly test the capacity for each type i receptor to be activated by type II receptors and, therefore, perform its kinase function. I will also determine non- kinase based requirements for BMPR1A in forming the receptor complex. Finally, i will define mechanisms of receptor trafficking in the gastrula, characterizing where and through which pathways receptors are trafficked to and from the cell membrane. I will then functionally test the requirements for trafficking on BMP signaling levels and dorsoventral patterning by disrupting trafficking pathways. Together, these studies will elucidate specialized requirements for BMP receptors in signal transduction.

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Quick answers

Who received award F32HD114468?

F32HD114468 was awarded to The Trustees Of The University Of Pennsylvania by National Institute of Child Health and Human Development (National Institutes of Health) on August 10, 2024.

How much is award F32HD114468 worth?

$652,592 has been obligated on F32HD114468.

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