Deciphering the molecular landscape of frontotemporal lobar degeneration: A network-based proteomic approach - PROJECT SUMMARY/ABSTRACT This K23 career development award aims to support Dr. Rowan Saloner in acquiring the expertise to become a leading clinical researcher focused on unraveling the neurobiological underpinnings of clinical progression in frontotemporal lobar degeneration (FTLD), Alzheimer's disease (AD), and other related dementias (ADRD), Dr. Saloner is a clinical neuropsychology postdoctoral fellow transitioning to faculty at the University of California, San Francisco, Memory and Aging Center (MAC), This K23 will focus on large-scale proteomics, clinical characterization, and bioinformatics to identify fluid biomarker signatures of FTLD and their relationship to disease progression. Through the enriched multidisciplinary training environment at the MAC, Dr. Saloner aims to accomplish the following training goals: 1) clinical integration of deep molecular phenotyping of ADRD; 2) big data/bioinformatics; and 3) scientific leadership, Dr. Saloner will translate his K23 experience into future R01 efforts to integrate high-dimensional biological tools with detailed clinical phenotyping to refine personalized biomarkers for diagnosis, prognosis, and therapeutic target engagement in ADRD. Dr. Saloner has assembled an exemplary mentorship team with expertise in neurobehavioral aging (Primary Mentor Dr, Kaitlin Casaletto ), ADRD fluid biomarkers (Co-Primary Mentor Dr. Adam Boxer), proteomics (Co-Mentor Dr, Nicholas Seyfried), biostatistics (Co-Mentor Dr. John Karnak), disease progression modeling (Collaborator Dr. Adam Staffaroni), FTLD biology (Advisor Dr. Jennifer Yokoyama), and professional development (Advisor Dr. Joel Kramer). The central rationale is that the most potent therapeutics for ADRD will modify molecular targets that change early in disease and have downstream effects on neuron loss and cognitive decline. Cutting-edge proteomic platforms that measure thousands of proteins in a single biospecimen sample have advanced understanding of AD biology in living humans. However, far less is known regarding the molecular evolution of FTLD, a common cause of young-onset dementia for which there are no effective therapies. The proposed study will leverage large-scale proteomics in cerebrospinal fluid (CSF) and plasma to identify protein signatures that precede and predict brain atrophy and cognitive decline in carriers of autosomal dominant FTLD mutations, who represent an ideal population to study early ADRD biomarkers. Antemortem CSF and plasma proteomic data in sporadic, pathology-confirmed FTLD will also be leveraged to determine the degree to which genetically-derived protein signatures translate to sporadic FTLD, which represents the majority of FTLD cases. Examining deep molecular screening tools in relation to FTLD progression strongly aligns with Actions 1.B.1 ( Expand research to identify the molecular and cellular mechanisms underlying Alzheimer's disease and related dementias ) and 1.C, 1 ( Identify imaging and biomarkers to monitor disease progression ) of the 2022 National Plan to Address Alzheimer's Disease. Successful completion of study aims will advance discovery of early FTLD biology in humans and identify targets for the development of urgently needed FTLD biomarkers and treatments.
