Project Grant K08HL173632

EXPLOITING NEOINTIMAL AND VASCULAR SMOOTH MUSCLE CELL HETEROGENEITY TO REVEAL MECHANISMS DRIVING VENOUS NEOINTIMAL GROWTH AND VASCULAR REMODELING IN PEDIATRIC PULMONARY HYPERTENSION - ABSTRACT PEDIATRIC PULMONARY HYPERTENSION (PPH) IS A PROGRESSIVE AND INCURABLE DISEASE HALLMARKED BY ABNORMAL DEVELOPMENT, MUSCULARIZATION AND BLOCKAGE OF SMALL PULMONARY VESSELS BY THE FORMATION OF OBSTRUCTIVE 'NEOINTIMAL LESIONS'. WHILE MOST RESEARCH HAS FOCUSED ON ARTERIAL DISEASE, VENOUS CHANGES INCLUDING NEOINTIMA, ARE DESCRIBED IN NEARLY ALL FORMS OF PPH BUT LITTLE IS KNOWN ABOUT WHAT CONTROLS VEIN NEOINTIMA FORMATION. AVAILABLE THERAPIES DO NOT TARGET LESION GROWTH, NEITHER PREVENT NOR REVERSE DISEASE, AND ARE CONTRAINDICATED WHEN VEIN REMODELING PREDOMINATES. EARLY EVIDENCE SUGGESTS NOVEL HETEROGENEITY AMONG PULMONARY VASCULAR SMOOTH MUSCLE CELLS (VSMCS) AND NEOINTIMA, BUT THE MOLECULAR CONTROL AND CONTRIBUTION OF THESE SUBSETS IN PPH REMAINS UNKNOWN. UNDERSTANDING THE BIOLOGY OF POST-CAPILLARY VASCULAR REMODELING AND, MORE GENERALLY, HOW HETEROGENEOUS VSMC AND NEOINTIMAL SUBSETS CONTRIBUTE TO PPH HAS THE POTENTIAL TO SIGNIFICANTLY ADVANCE THE UNDERSTANDING OF THE CELLULAR AND MOLECULAR CONTROLS OF PATHOLOGIC VASCULAR REMODELING IN PPH. IN AIM 1, DR. LEA STEFFES WILL TRAIN WITH MENTORS DR. MAYA KUMAR IN MOUSE TRANSGENICS, CUTTING-EDGE IMAGING AND QUANTITATION TECHNIQUES AND DR. MARK KRASNOW IN ADVANCED BIOCOMPUTATIONAL ANALYSIS TO DEFINE TRANSCRIPTOMIC HETEROGENEITY BETWEEN PRE- AND POST-CAPILLARY NEOINTIMA AND PROVIDE THE FIRST GENOMIC-WIDE CHARACTERIZATION OF VEIN NEOINTIMA. IN ADDITION TO AN IN VIVO PHARMACOLOGIC INHIBITION STUDY IN MICE USING TOOLS DEVELOPED AND PUBLISHED BY DRS. STEFFES AND KUMAR, IN AIM 2, DR. STEFFES WILL TRAIN WITH ADVISOR DR. DAVID CORNFIELD TO PERFORM A BROAD IN VITRO SCREEN OF VSMC GROWTH MODULATORS ON VEIN NEOINTIMA CELLS. WITH TRAINING IN HUMAN PULMONARY VASCULAR HISTOPATHOLOGY FROM ADVISORS DRS. SERENA TAN AND CSABA GALAMBOS, AIM 3 WILL CONNECT DR. STEFFES'S RESEARCH AND CLINICAL EXPERTISE BY INTERROGATING THE ROLE OF TWO NOVEL DEVELOPMENTAL VSMC SUBSETS IN HERITABLE PPH. THE CANDIDATE TRAINING PLAN PROVIDES A COMPLIMENTARY SKILLSET OF IN VITRO INVESTIGATION, BIO-COMPUTATIONAL ANALYSIS, AND HUMAN LUNG VASCULAR HISTOPATHOLOGY TRAINING TO INTERROGATE THE CELL-SPECIFIC BEHAVIORS AND MOLECULAR SIGNATURES OF PATHOLOGIC CELL TYPES (VEIN NEOINTIMA, AIMS 1 & 2 AND DEVELOPMENTAL VSMC SUBSETS, AIM3) INTEGRAL TO PPH. MENTOR DR. MAYA KUMAR IS A THOUGHT-LEADER IN THE USE OF ADVANCED MOUSE GENETICS AND GENOMIC TOOLS TO INTERROGATE PATHOLOGIC PULMONARY VASCULAR BIOLOGY. CO-MENTOR DR. MARK KRASNOW (SINGLE CELL ANALYSIS) AND ADVISORS DR. DAVID CORNFIELD (IN VITRO ANALYSIS) AND DR. SERENA TAN (HUMAN LUNG HISTOPATHOLOGY) AND DR. CSABA GALAMBOS (PEDIATRIC PPH PATHOLOGY) OFFER COMPLEMENTARY EXPERTISE. THE ENVIRONMENT AT STANFORD UNIVERSITY IS RENOWNED FOR COLLABORATIVE AND INNOVATIVE RESEARCH. SUPPORTED BY THIS INFRASTRUCTURE, CANDIDATE DR. STEFFES HAS DEMONSTRATED TREMENDOUS ACADEMIC GROWTH WITH 9 PUBLICATIONS INCLUDING 5 AS FIRST-AUTHOR SINCE 2020. IN SUMMARY, THIS STRONG MENTORING ENVIRONMENT AND TRAINING PLAN ARE ANTICIPATED TO FULLY PREPARE DR. STEFFES TO LAUNCH HER INDEPENDENT CAREER. THE PROPOSED STUDIES WILL OFFER MECHANISTIC INSIGHTS INTO PEDIATRIC PULMONARY VASCULAR PATHOGENESIS, AND MAY IDENTIFY THERAPEUTIC TARGETS TO IMPROVE THE LIVES OF CHILDREN WITH PPH.