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From its inception, BD² set out to promote transformative and meaningful collaboration to drive discovery and treatment improvements so all those living with bipolar disorder can thrive. To that end, the BD² Collaboration Projects empower multidisciplinary teams—including experts in genetics, neurobiology, and pharmacology—to advance understanding of the disorder’s complexities. By fostering collaboration across BD² program teams, these grants encourage our network of scientists, researchers, and clinicians to pool their expertise, insights, and resources to drive impactful advances.

Drug Prediction and Validation from Single Cell Multi-Omics in Brain Organoid Systems

Bipolar disorder is a highly heritable mental disorder that affects millions of people worldwide. The currently available pharmacological treatments are not effective in alleviating the symptoms faced by many individuals with bipolar and the field has a need for high-throughput drug screens that can identify new candidates. To accelerate this process, Jenny Tam, PhD from the Discovery Research team, and Panos Roussos, PhD from the Brain Omics Platform are leveraging the largest single-cell omics level datasets from bipolar and control patients with novel drug prediction algorithms. These teams will address key research gaps, fostering innovations in drug discovery and precision medicine.

“This unique collaboration with Team Tam is incredibly exciting. Combining our extensive single-cell multi-omic data with their advanced brain organoid platform creates an unprecedented opportunity to prioritize and test the efficacy of drug candidates for BD. This has the potential to significantly accelerate the development of novel therapies.”
– Donghoon Lee, PhD

“The group at Mt. Sinai brings an incredible degree of expertise, experience and access to multi-omic datasets of the human brain that complements extraordinarily well with our brain organoid platform. This collaborative effort was only made possible with the support of the BD² initiative, providing our teams with a unique opportunity to pressure test prediction models and accelerate discoveries into the clinic.”
– Ninning Liu, PhD

Mitochondrial Dysfunction as a Mechanism to Explain Sleep Dysregulation in Bipolar Disorder

There is growing evidence that familial mitochondrial genetic disorders or genetic conditions can play a part in driving bipolar disorder. Notably, there are several genes that contribute to mitochondrial alterations that are also implicated in bipolar disorder. For this reason, Julie Kauer, PhD from the Discovery Research team, is partnering with Elizabeth Jonas, MD to investigate the role of mitochondrial dysfunction and gene regulation in sleep and mood disruptions, symptomatic behaviors of bipolar. Using cutting-edge CRISPR technology, neuroimaging, and proteomics, the teams aim to unravel how genetic and mitochondrial abnormalities contribute to bipolar disorder symptoms. Their efforts will lay the foundation for targeted treatments and tools to advance diagnosis and management.

“We are very enthusiastic about the Kauer/Jonas/de Lecea collaborative effort, as our study represents the first time the marked sleep abnormalities that characterize BD will be correlated with mitochondrial dysregulation, a biomarker for BD. In mice expressing BD-linked genes, we will attempt to ameliorate sleep abnormalities by enhancing mitochondrial metabolic efficacy, suggesting new treatment strategies.”
– Julie Kauer, PhD

Proximity Labeling Neuroprotemic Investigation of Clock Loss in VTA DA Neurons

Protein networks are the fundamental machines in neurons that execute cellular functions and malfunction in disease. To that end, Yevgenia Kozorovitskiy, PhD, and Lief Fenno, MD, PhD from the Discovery Research team and Matthew MacDonald, PhD from the Brain Omics Platform are collaborating to leverage new molecular tools that allow for the large-scale study of proteins at the cellular level. They will use this technology in a genetic model of bipolar disorder to assess proteomic changes associated with genomic alterations, which can drive alterations in neuronal activity and downstream behaviors. This project will inform the interpretation of protein network mapping in patient tissue, helping to sort out alterations linked to genetic risk, behavioral risk, and disease burden.

Transcriptomic Convergence of Bipolar Disorder Risk Genes in Human Neurons

Dozens (perhaps hundreds) of genetic variants collectively underlie risk for bipolar disorder, although it remains unclear how such diverse variations lead to shared clinical outcomes. It is possible that this large number of variants converge down onto a smaller number of cellular pathways or functions, that result in the same clinical outcome despite originating from different genetic loci. To address this, Hongying Shen, PhD from the Discovery Research team and Ben Neale, PhD from the Genetics Platform, are identifying common pathways affected by both common and rare genetic risk variants and probing those prioritized pathways with targeted drug candidates. Their collaboration will provide crucial insights into the functional mechanisms underlying bipolar disorder, making improved novel and tailored therapeutic strategies possible.

“The Collaboration Project grant through the BD² network, expanding on our ongoing work with local functional genomics expert at Yale Kristen Brennand and forging an exciting new partnership with Ben Neale’s genetics team, promises to reveal transformative insights into the impact of newly discovered disease-risk genes on the neuronal transcriptional landscape.”
– Hongying Shen, PhD

The BD² Collaboration Projects represent a major leap forward, paving the way for transformative advancements in the diagnosis, treatment, and understanding of this complex condition. These grants intentionally incorporate joint efforts, tackling interconnected research questions with the breadth and expertise of the BD² network. They play a crucial role within the broader BD² model, which is driven by individuals passionate about improving lives and bringing hope to those with bipolar disorder.