R01HL164581

Elucidating the structural insights into the BMP receptor mutations in PAH - Project Summary/Abstract

Pulmonary arterial hypertension (PAH) is a progressive disease that leads to death in 3 years if untreated. PAH is characterized by remodeling and eventually occlusion of the pulmonary arteries, followed by high PA pressure and right heart failure.

Heterozygous mutations in the bone morphogenetic protein receptor type 2 gene (BMPR2) are the leading genetic cause of PAH. In patients with BMPR2 mutations, PAH develops years earlier, and in a more severe form, than in patients with normal BMPR2.

Notwithstanding the recent progress in identifying the molecular and cellular consequences of BMPR2 mutations, no targeted therapy for BMPR2 carriers exist, nor the dire need for novel therapies has been met.

A well-supported model of BMP signaling starts with a ligand binding to a group of transmembrane serine/threonine receptor kinases comprised of two type 1 receptor (BMRPI) and two type 2 receptors (BMPR2). The heterotetrameric active BMP receptor complex phosphorylates SMAD proteins that carry the signal downstream to the nucleus.

Gaps in this model include lack of understanding why the receptors need to be organized in a heterotetramer configuration to be active, and how the receptor kinases are activated. Consequently, our understanding of prevalent PAH mutations that localize to the BMPR2 intracellular regions remains unsatisfactory and prohibitive from advancing PAH-targeted therapies.

Our recent studies have led to a discovery that kinase domain of BMPR2 forms a heterodimer with a type 1 BMP receptor kinase. Formation of the heterodimer is not sufficient to activate the type 1 kinase but is essential for ligand-induced receptor signaling, suggesting its essential role in assembly of the active receptor tetramer.

Importantly, several BMPR2 mutants linked to PAH map to the heterodimer interface and inhibit ligand-induced downstream SMAD signaling, supporting the physiological significance of the heterodimer interface.

The goal of this application is to elucidate the molecular underpinnings of BMP receptor kinase activation and elucidate how poorly understood BMPR2 mutations trigger PAH by: (i) dissecting the role of the type 1/type 1 kinase oligomerization in the catalytic activation of the BMP receptor complex, downstream signaling, and vascular homeostasis, and (ii) gaining the structural understanding of the active type 1/type 2 kinase domain complexes alone and in the context of full-length BMP receptor tetramers.

Upon completion, this study will define the significance of the non-catalytic interfaces present on BMP receptor kinases and provide insights into how BMPR2 mutations perturb the type 1/type 2 kinase interactions resulting in PAH. This knowledge will provide a platform for the development of innovative novel PAH therapies.

San Francisco Regents Of The University Of California

THE NATIONAL HEART, LUNG, AND BLOOD INSTITUTE (NHLBI) PROVIDES GLOBAL LEADERSHIP FOR A RESEARCH, TRAINING, AND EDUCATION PROGRAM TO PROMOTE THE PREVENTION AND TREATMENT OF HEART, LUNG, AND BLOOD DISEASES AND ENHANCE THE HEALTH OF ALL INDIVIDUALS SO THAT THEY CAN LIVE LONGER AND MORE FULFILLING LIVES. THE DIVISION OF LUNG DISEASES SUPPORTS RESEARCH AND RESEARCH TRAINING ON THE CAUSES, DIAGNOSIS, PREVENTION, AND TREATMENT OF LUNG DISEASES AND SLEEP DISORDERS. RESEARCH IS FUNDED THROUGH INVESTIGATOR-INITIATED AND INSTITUTE-INITIATED GRANT PROGRAMS AND THROUGH CONTRACT PROGRAMS IN AREAS INCLUDING ASTHMA, BRONCHOPULMONARY DYSPLASIA, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, CYSTIC FIBROSIS, RESPIRATORY NEUROBIOLOGY, SLEEP AND CIRCADIAN BIOLOGY, SLEEP-DISORDERED BREATHING, CRITICAL CARE AND ACUTE LUNG INJURY, DEVELOPMENTAL BIOLOGY AND PEDIATRIC PULMONARY DISEASES, IMMUNOLOGIC AND FIBROTIC PULMONARY DISEASE, RARE LUNG DISORDERS, PULMONARY VASCULAR DISEASE, AND PULMONARY COMPLICATIONS OF AIDS AND TUBERCULOSIS. THE DIVISION IS RESPONSIBLE FOR MONITORING THE LATEST RESEARCH DEVELOPMENTS IN THE EXTRAMURAL SCIENTIFIC COMMUNITY AS WELL AS IDENTIFYING RESEARCH GAPS AND NEEDS, OBTAINING ADVICE FROM EXPERTS IN THE FIELD, AND IMPLEMENTING PROGRAMS TO ADDRESS NEW OPPORTUNITIES. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION; USE SMALL BUSINESS TO MEET FEDERAL RESEARCH AND DEVELOPMENT NEEDS; FOSTER AND ENCOURAGE PARTICIPATION IN INNOVATION AND ENTREPRENEURSHIP BY SOCIALLY AND ECONOMICALLY DISADVANTAGED PERSONS; AND INCREASE PRIVATE-SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT FUNDING. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE TECHNOLOGICAL INNOVATION; FOSTER TECHNOLOGY TRANSFER THROUGH COOPERATIVE R&D BETWEEN SMALL BUSINESSES AND RESEARCH INSTITUTIONS, AND INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL R&D.

93.837 - Cardiovascular Diseases Research

National Heart Lung and Blood Institute (NHLBI) [HHS - NIH]

San Francisco, California 941432156 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 291% from $805,232 to $3,145,757.