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Principal Investigator: ADITYA Devidas Mahadevan
Organization: UNIVERSITY OF FLORIDA
Fiscal Year: 2024
Award: $43,163
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY/ABSTRACT
The primary goal of this proposal is to provide a framework of methodologically-diverse, and clinically-inclined,
investigative training that will prepare the principal investigator for a successful career as a translational
physician-scientist. In addition to MD/PhD-specific professional development and expanded clinical/translational
training, much of this preparation will come from technical education gained from the execution of this proposal’s
research aims. These aims seek to broadly understand the placental correlates of fetal congenital heart defects
(CHDs) in pregnancies affected by pregestational maternal diabetes mellitus (DM). It is recognized that the
placenta plays a critical role in the development of fetal CHDs in early pregnancy, although this role is poorly
understood. DM-affected pregnancies also have a pronounced phenotype of placental dysfunction, although the
mediators of this also remain unknown. Additionally, DM-affected pregnancies are at substantially elevated risk
of developing fetal CHDs and, for certain subtypes of CHD, carry an RR as high as 13.8. These CHDs represent
a large percentage of critical and surgery-necessitating defects and are particularly high-burden, as they come
with risk of additional malformations, neonatal hypoglycemia, preterm birth, and other perinatal complications.
These complications, many of which are also seen in DM pregnancies, come downstream of cyclical
exacerbations of placental dysfunction due to CHD-induced fetal hemodynamic changes. Given this,
investigation of the pronounced changes in placental function seen in DM and/or CHD-affected pregnancies
could yield extremely impactful information for both diagnostic and prognostic management of CHDs in diabetic
pregnancies. The identification of pathway-level molecular changes, and their clinical associations, in
pregnancies affected by DM, fetal CHDs, and both (DM+CHD) will produce novel and foundational information
that could change the paradigm of perinatal care in these pregnancies. The overarching hypothesis of this project
is that similar profiles of angiogenic and inflammatory molecular dysfunction, and resulting clinical pathology, will
be observed in both maternal DM-affected and fetal CHD-affected pregnancies, and that this dysfunction will be
particularly exacerbated in DM-affected pregnancies that also develop fetal CHD. This hypothesis will be tested
via two aims. One aim will use large-scale institutional health data to assess the perinatal risk of common
obstetric and neonatal complications in DM+CHD pregnancies relative to those affected by either pathology in
isolation. The other will characterize the cell type-specific molecular dysfunction of DM, CHD, and DM+CHD
placentas using high-throughput RNA sequencing, western blotting, and immunohistochemistry. In completing
this training plan, and the scientific aims it includes, the applicant will receive critical didactic and experiential
training necessary to achieve the long-term goal of their career, which is to multimodally improve the prevention
and management of CHD- and DM-affected pregnancies, through improved perinatal risk-assessment, targeted
prenatal therapy/supplementation, or serum biomarker identification for early diagnosis.
Terms: <0-11 years old><A5 Antigen><Affect><Biological Markers><Birth Defects><Blood Serum><Blood Vessels><Body Tissues><Cardiac><Causality><Cell Communication and Signaling><Cell Signaling><Cells Placenta-Tissue><Characteristics><Child><Child Youth><Children (0-21)><Clinical><Clinical Pathology><Code><Coding System><Congenital Abnormality><Congenital Anatomical Abnormality><Congenital Cardiac Defects><Congenital Defects><Congenital Deformity><Congenital Heart Defects><Congenital Malformation><Data Bases><Databases><Defect><Deposit><Deposition><Developing fetus><Development><Diabetes Mellitus><Diabetic mother><Diagnosis><Diagnostic><Discipline of obstetrics><Disease><Disorder><Doctor of Philosophy><Dysfunction><EPH Gestosis><Early Diagnosis><Endothelium><Epithelium><Etiology><Fetal Development><Fetal Growth Restriction><Fetal Growth Retardation><Fetal Therapies><Fibrin><Formalin><Functional disorder><Future><Gene Transcription><General Population><General Public><Genes><Genetic Transcription><Gestation><Goals><Heart><High-Throughput RNA Sequencing><Histologic><Histologically><Human><Hyperglycemia><Hypoxia><Hypoxic><IUGR><Immunoblotting><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Incidence><Infant><Infant Mortality><Infant Mortality Total><Inflammatory><Institution><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Intrauterine Growth Retardation><Investigation><Link><Mediating><Mediator><Mesenchymal><Methodology><Miscarriage><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Morphology><Mothers><NRP1><NRP1 Protein><NRP1 gene><Neonatal><Neonatal Hypoglycemia><Neuropilin-1><Normal Placentoma><Npn-1 Protein><Obstetrics><Ontology><Operative Procedures><Operative Surgical Procedures><Organ><Outcome><Oxygen Deficiency><Paraffin Embedding><Pathology><Pathway interactions><Pattern><Perinatal><Perinatal Care><Perinatal Mortalities><Perinatal lethality><Perinatal mortality demographics><Peripartum><Ph.D.><PhD><Phenotype><Physiology><Physiopathology><Placenta><Placenta Embryonic Tissue><Placental Development><Placentation><Placentome><Play><Pre-Eclampsia><Preeclampsia><Pregnancy><Pregnancy Complications><Pregnancy Toxemias><Pregnancy in Diabetes><Pregnancy in Diabetics><Premature Birth><Prematurely delivering><Preparation><Preterm Birth><Prevention><Principal Investigator><Process><Proteins><Proteinuria-Edema-Hypertension Gestosis><RNA Expression><Relative Risks><Research Proposals><Resolution><Risk><Risk Assessment><Risk Management><Role><Scientist><Sema III Receptor><Semaphorin III Receptor><Serum><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Spontaneous abortion><Structure><Supplementation><Surgical><Surgical Interventions><Surgical Procedure><Testing><Thrombosis><Tissue Embedding><Tissues><Training><Transcription><Translations><Umbilical Region><Umbilical vein><Umbilicus><VEGF165R><Vascular Diseases><Vascular Disorder><Vascular Endothelial Cell Growth Factor 165 Receptor><Vascular Endothelium><Villous><Vocational Education><Vocational Training><Western Blotting><Western Immunoblotting><adverse consequence><adverse outcome><angiogenesis><bio-markers><biologic marker><biological signal transduction><biomarker><biomarker identification><blood vessel disorder><career><causation><cell type><clinical risk><complications during pregnancy><cytotrophoblast><data base><death among infants><death in first year of life><death in infancy><death in infants><developmental><diabetes><diabetic><disease causation><early detection><early pregnancy><fetal><fetus therapy><health data><health record><hemodynamics><hyperglycemic><identification of biomarkers><identification of new biomarkers><impaired fetal growth><improved><in utero><in utero therapy><infant death><infant demise><infantile death><infantile hypoglycemia><interventional strategy><intra-uterine growth restriction><intra-uterine growth retardation><intrauterine growth restriction><kids><malformation><marker identification><maternal diabetes><maternal morbidity><mortality><mortality in infants><multi-modality><multimodality><neonatal morbidity><newborn morbidity><novel><obstetric outcomes><pathophysiology><pathway><perinatal complications><perinatal deaths><perinatal outcomes><placenta morphology><placental morphology><pre-eclamptic><pregnancy toxemia/hypertension><pregnancy-related complications><premature childbirth><premature delivery><prenatal><prenatal growth disorder><prenatal therapy><preparations><preterm delivery><prevent><preventing><prognostic><protein blotting><protein expression><resolutions><social role><surgery><technical education><thrombotic disease><thrombotic disorder><translation><translational clinician><translational physician><unborn><vascular><vascular abnormality><vascular dysfunction><vasculopathy><youngster>