Project Description
Objectives and Methodology The primary objective of this research is to develop a novel, brain-penetrant histone deacetylase 2 (HDAC2) inhibitor aimed at enhancing memory formation and treating cognitive deficits associated with Alzheimer’s disease and other neurodegenerative conditions. HDAC2 plays a key role in regulating histone acetylation, an epigenetic modification critical for gene transcription involved in long-term memory formation. This research focuses on the design and development of a new disulfide-based compound, JRM-28, which is inspired by the structure of the FDA-approved HDAC inhibitor romidepsin. JRM-28 is engineered to overcome the limitations of current HDAC inhibitors, such as poor blood-brain barrier (BBB) permeability and systemic toxicity. Methodology includes:
• Organic Synthesis: Design and synthesis of disulfide-based analogs of HDAC2 inhibitors.
• Purification and Characterization: Use of chromatography techniques and spectroscopic methods to purify and identify synthesized compounds.
• Biochemical Evaluation: Measuring histone H3 acetylation levels to determine HDAC2 inhibition.
• Pharmacokinetics: Determining the compound’s blood-brain barrier permeability.
• Behavioral Correlation: Testing compound efficacy through memory formation studies in preclinical models.
Tasks and Responsibilites
As a student researcher, you will work alongside graduate students and contribute to the development and evaluation of JRM-28. Your specific responsibilities will include:
• Synthesizing Analogs: Assisting in the design and chemical synthesis of structural analogs of JRM-28 to optimize potency and pharmacological properties.
• Running Purification Columns: Operating silica gel and reverse-phase chromatography columns to purify reaction products.
• Spectroscopic Characterization: Assisting in techniques such as NMR, IR, and MS to characterize the structure and purity of synthesized compounds.
• Histone Acetylation Assays: Helping with biochemical assays to assess the impact of JRM-28 and its analogs on histone H3 acetylation levels.
• Data Logging and Analysis: Recording and organizing experimental data, and assisting with the interpretation of results.
• General Lab Support: Preparing reagents, maintaining laboratory cleanliness, and ensuring the proper functioning of lab equipment.