Post Doctoral Fellow-MSH-30001-002

Mount Sinai Health System • New York, NY

1d

About The Position

This project aims to develop and investigate human cortical brain organoids (hCBOs) derived from induced pluripotent stem cells (iPSCs) to elucidate molecular mechanisms and assess potential treatment strategies for PDHA1-related pyruvate dehydrogenase complex (PDHc) deficiency. The study will integrate structural, metabolic, and functional assessments to identify disease-related alterations and evaluate therapeutic interventions. The first three months will focus on generating hCBOs from patient-derived and control iPSCs. From months four to six, neuronal structure and development will be characterized at the molecular level. Single-cell RNA sequencing (scRNA-seq) will be performed to identify cell-type-specific transcriptional alterations in PDHA1-deficient organoids. Parallel metabolic analyses will begin, using metabolomic and proteomic profiling to determine how PDHA1 deficiency affect glycolysis, oxidative phosphorylation, and overall metabolic function of hCBOs. During months seven to nine, functional assessments will be conducted to investigate neuronal network activity. Multi-electrode array (MEA) recordings will evaluate extracellular neuronal firing patterns, burst frequency, and network synchronicity, while calcium imaging will assess intracellular neuronal excitability. Additional metabolic assays, such as oxygen consumption rate (OCR) measurements, will further characterize energy metabolism deficits in PDHA1-deficient organoids. From months ten to twelve, targeted therapeutic interventions will be introduced to determine their efficacy in restoring metabolic and functional deficits. Candidate treatments will include pyruvate supplementation, dichloroacetate (DCA), and alternative metabolic modulators to bypass PDHc dysfunction. The impact of these treatments will be evaluated by comparing structural, metabolic, and functional parameters between treated and untreated PDHA1-deficient organoids. Final multi-omic data integration will be performed to identify key molecular pathways involved in the disease and response to treatment. The final month will be dedicated to data analysis, manuscript preparation, and development of presentations for conferences and funding applications. The project will culminate in a comprehensive dataset linking neuronal structure, metabolism, and activity in PDHA1-related PDHc deficiency, providing insights into potential therapeutic strategies for this disorder.

Requirements

• PHD
• Prior clinical rotations in field of study

Responsibilities

• Generating hCBOs from patient-derived and control iPSCs.
• Characterizing neuronal structure and development at the molecular level.
• Performing single-cell RNA sequencing (scRNA-seq) to identify cell-type-specific transcriptional alterations.
• Conducting metabolic analyses using metabolomic and proteomic profiling.
• Investigating neuronal network activity using multi-electrode array (MEA) recordings and calcium imaging.
• Performing metabolic assays such as oxygen consumption rate (OCR) measurements.
• Introducing targeted therapeutic interventions to determine their efficacy.
• Evaluating the impact of treatments by comparing structural, metabolic, and functional parameters.
• Performing multi-omic data integration to identify key molecular pathways.
• Analyzing data, preparing manuscripts, and developing presentations for conferences and funding applications.

What This Job Offers

• Job Type: Full-time
• Career Level: Entry Level
• Education Level: Ph.D. or professional degree