RM1MH132651

UCLA High-Throughput Neuropsychiatric Disorder Phenotyping Center (UCLA HT-NPC) - Project Summary/Abstract

Human genetic studies have identified hundreds of genes contributing to neuropsychiatric and neurodevelopmental disease (NPD) risk. However, the normal function of most genes and the consequences of their absence or reduction on neurodevelopment and neural function remain unknown. This project aims to address the challenges of understanding the potential functions of hundreds of NPD genes through the development of a high-throughput neuropsychiatric disease phenotyping center (UCLA HT-NPC).

The UCLA HT-NPC is driven by the collaboration of nine highly collaborative investigators (Aharoni, Bhaduri, Damoiseaux, Geschwind, Golshani, Kitai, Luo, Novich, and Wells) and two substantial core facilities (UCLA Molecular Screening Shared Resource and the Human Stem Cell and Genome Engineering Center). Through a tiered approach, the project combines high-throughput and high-value quantitative phenotyping with stem cell engineering to characterize the functional consequences of NPD gene knockouts (null alleles), which is an essential initial step in understanding disease pathways.

In the first step, the project will rapidly generate null alleles for 250 genes chosen by the consortium using a rapid, high-throughput lentiviral-based system in human embryonic stem cells (HESCs). Viability and neural induction potential will be assessed, and quantitative phenotyping will be conducted using RNA-Seq on all lines. Genes that pass the viability and neural induction tests will be used to produce clonal null human induced pluripotent stem cell (hiPSC) lines (male and female) for downstream phenotyping and wider distribution to the community.

Subsequently, the project will perform high-throughput, quantitative, multi-scale phenotyping at the molecular, morphological, and physiological levels in both 2D and 3D hiPSC-based models of human cortical development. The project leverages the strengths and scalability of each model to enable the performance of single-nucleus RNA sequencing (snRNA-Seq) and bulk RNA-Seq, measurement of maturation, morphology, and synaptic density of neural cells using automated imaging (including the multiplexed, protein-based CODEX/PhenoCycler platform), and characterization of neuronal activity and synchronization through optical recordings using custom-built mini-scope arrays (StimScope).

By using multiple systems (e.g., HESC/hiPSC, gene editing, 2D and 3D cultures), the project tests biological reproducibility across systems and technical reproducibility through replication. The use of experimentally validated, quantitative phenotypes across multiple scales of analysis facilitates data sharing and comparisons with other SSPSYGENE investigators and provides a template for the field more broadly.

Los Angeles University Of California

THE MISSION OF THE NATIONAL INSTITUTE OF MENTAL HEALTH (NIMH) IS TO TRANSFORM THE UNDERSTANDING AND TREATMENT OF MENTAL ILLNESSES THROUGH BASIC AND CLINICAL RESEARCH, PAVING THE WAY FOR PREVENTION, RECOVERY, AND CURE. WE FULFILL THIS MISSION BY SUPPORTING AND CONDUCTING RESEARCH ON MENTAL ILLNESSES, HEALTH SERVICES, AND THE UNDERLYING BASIC SCIENCE OF THE BRAIN AND BEHAVIOR; SUPPORTING THE TRAINING OF SCIENTISTS TO CARRY OUT BASIC AND CLINICAL MENTAL HEALTH RESEARCH; AND COMMUNICATING WITH SCIENTISTS, PATIENTS, PROVIDERS, AND THE PUBLIC ABOUT MENTAL HEALTH RESEARCH ADVANCES AND PRIORITIES. IN MAY 2024, NIMH RELEASED ITS STRATEGIC PLAN FOR RESEARCH. THE STRATEGIC PLAN BUILDS ON THE SUCCESSES OF PREVIOUS NIMH STRATEGIC PLANS BY PROVIDING A FRAMEWORK FOR SCIENTIFIC RESEARCH AND EXPLORATION, AND ADDRESSING NEW CHALLENGES IN MENTAL HEALTH.THE NEW STRATEGIC PLAN OUTLINES FOUR HIGH-LEVEL GOALS: GOAL 1: DEFINE THE BRAIN MECHANISMS UNDERLYING COMPLEX BEHAVIORS GOAL 2: EXAMINE MENTAL ILLNESS TRAJECTORIES ACROSS THE LIFESPAN GOAL 3: STRIVE FOR PREVENTION AND CURES GOAL 4: STRENGTHEN THE PUBLIC HEALTH IMPACT OF NIMH-SUPPORTED RESEARCH THESE FOUR GOALS FORM A BROAD ROADMAP FOR THE INSTITUTES RESEARCH PRIORITIES OVER THE NEXT FIVE YEARS, BEGINNING WITH THE FUNDAMENTAL SCIENCE OF THE BRAIN AND BEHAVIOR, AND EXTENDING THROUGH EVIDENCE-BASED SERVICES THAT IMPROVE PUBLIC HEALTH OUTCOMES.

93.242 - Mental Health Research Grants

National Institute of Mental Health (NIMH) [HHS - NIH]

Los Angeles, California 900244200 United States

Single Zip Code

Scalable and Systematic Neurobiology of Psychiatric and Neurodevelopmental Disorder Risk Genes: Assay and Data Generation Centers (RM1 Clinical Trial Not Allowed) (RFA-MH-22-111)

Amendment Since initial award the total obligations have increased 293% from $1,652,209 to $6,493,976.