Diversity Supplement: Single Cell Analyses of Neuroimmune Dysfunctions in the Thalamocortical Circuit in FTLD

点击翻译按钮获取中文摘要

Project Summary Frontotemporal dementia (FTD) is an early onset neurodegenerative disease, and the second most common cause of dementia in patients 60 years or younger. The majority of familial FTD are caused by intronic hexanucleotide (CCCCGG) repeat expansion in chromosome 9 open reading frame 72 (C9orf72) gene and by dominant mutations in the Progranulin (GRN) gene, which account for 25% and 15% of familial FTD cases, respectively. These mutations cause haploinsufficiency in both genes and lead to abnormal protein aggregation involving RNA binding protein TDP-43 in neuronal nuclei and cytoplasm. The goal of the parent grant (R01 AA027074-03) is to test the hypothesis that loss of PGRN disrupts neuroimmune interaction in the thalamo- cortical circuit in Grn-/- mice. The purpose of this Diversity Supplement is to expand the scope of the parent grant and characterize the potential interaction of C9orf72 and progranulin in neurodegeneration. To this end, the proposed trainee, Naznin Jahan – a 4th year graduate student in the BMS Graduate Program at UCSF, has established an aging cohort of C9orf72-/-, Grn-/-, and C9orf72-/-;Grn-/- double KO (DKO) mice. The trainee’s results showed that C9orf72-/-;Grn-/- DKO mice exhibit age-dependent neuroinflammation and neuronal loss that are more pronounced than those seen in C9orf72-/- and Grn-/- mice. These findings support the intriguing hypothesis that simultaneous loss-of-function (LOF) in C9orf72 and GRN genes synergistically disrupts glial homeostasis and promote neuronal degeneration in an age dependent manner. The scope of this Diversity Supplement includes (1) to determine the transcriptomic changes regulated by C9orf72 and Grn in glia-neuron homeostasis, and (2) to expand the transcriptomic data using in situ hybridization (ISH), immunohistochemistry and Western blots. In addition, this Diversity Supplement includes a well-defined 2-year timeline, a detailed Mentoring Plan, and Individual Career Development Plan (ICDP) that will significantly enhance the candidate’s research capabilities and complete her dissertation work on the genetic interactions that cause the age dependent neurodegeneration in mice. Working within the proposed timeline, this supplement will prepare the candidate for her long-term career goal as an academic scientist in the field of neuroimmune interaction and neurodegeneration.