Description
Using Human Cortical Brain Organoids to Uncover Molecular Mechanisms and Treatment Efficacy in PDHA1-Related PDHc Deficiency
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
Responsibilities
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 organoid 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.
Qualifications
Employer Description
Strength through Unity and Inclusion
The Mount Sinai Health System is committed to fostering an environment where everyone can contribute to excellence. We share a common dedication to delivering outstanding patient care. When you join us, you become part of Mount Sinai's unparalleled legacy of achievement, education, and innovation as we work together to transform healthcare. We encourage all team members to actively participate in creating a culture that ensures fair access to opportunities, promotes inclusive practices, and supports the success of every individual.
At Mount Sinai, our leaders are committed to fostering a workplace where all employees feel valued, respected, and empowered to grow. We strive to create an environment where collaboration, fairness, and continuous learning drive positive change, improving the well-being of our staff, patients, and organization. Our leaders are expected to challenge outdated practices, promote a culture of respect, and work toward meaningful improvements that enhance patient care and workplace experiences. We are dedicated to building a supportive and welcoming environment where everyone has the opportunity to thrive and advance professionally. Explore this opportunity and be part of the next chapter in our history.
About the Mount Sinai Health System:
Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with more than 48,000 employees working across eight hospitals, more than 400 outpatient practices, more than 300 labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time - discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it. Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients' medical and emotional needs at the center of all treatment. The Health System includes more than 9,000 primary and specialty care physicians; 13 joint-venture outpatient surgery centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and more than 30 affiliated community health centers. We are consistently ranked by U.S. News & World Report's Best Hospitals, receiving high "Honor Roll" status, and are highly ranked: No. 1 in Geriatrics, top 5 in Cardiology/Heart Surgery, and top 20 in Diabetes/Endocrinology, Gastroenterology/GI Surgery, Neurology/Neurosurgery, Orthopedics, Pulmonology/Lung Surgery, Rehabilitation, and Urology. New York Eye and Ear Infirmary of Mount Sinai is ranked No. 12 in Ophthalmology. U.S. News & World Report's "Best Children's Hospitals" ranks Mount Sinai Kravis Children's Hospital among the country's best in several pediatric specialties. The Icahn School of Medicine at Mount Sinai is ranked No. 11 nationwide in National Institutes of Health funding and in the 99th percentile in research dollars per investigator according to the Association of American Medical Colleges. Newsweek's "The World's Best Smart Hospitals" ranks The Mount Sinai Hospital as No. 1 in New York and in the top five globally, and Mount Sinai Morningside in the top 20 globally.
Equal Opportunity Employer
The Mount Sinai Health System is an equal opportunity employer, complying with all applicable federal civil rights laws. We do not discriminate, exclude, or treat individuals differently based on race, color, national origin, age, religion, disability, sex, sexual orientation, gender, veteran status, or any other characteristic protected by law. We are deeply committed to fostering an environment where all faculty, staff, students, trainees, patients, visitors, and the communities we serve feel respected and supported. Our goal is to create a healthcare and learning institution that actively works to remove barriers, address challenges, and promote fairness in all aspects of our organization.
Compensation
The Mount Sinai Health System (MSHS) provides salary ranges that comply with the New York City Law on Salary Transparency in Job Advertisements. The salary range for the role is $72500 - $80000 Annually. Actual salaries depend on a variety of factors, including experience, education, and operational need. The salary range or contractual rate listed does not include bonuses/incentive, differential pay or other forms of compensation or benefits.
| Location | New York, NY |
| Salary | $72,500–$80,000 Per Year |