Molecular Mechanisms and Therapeutics Development for Social and Communication Learning Deficits in NF1
Abstract
Rationale: Neurofibromatosis type 1 (NF1) is a genetic disease caused by a mutation in the NF1 gene. Although skin lesions and tumors are the most commonly recognized symptoms, far more children with NF1 suffer from significant incidence of learning difficulties, along with social and communication problems. Introducing a similar mutation of the Nf1 gene in mice provides an excellent animal model to understand this disease and to develop new treatments. Using such mutant mice, we recently demonstrated that the NF1-like mice (Nf1+/- mice) exhibit selective deficits in social memory and communication skills. We also demonstrated that blocking some specific molecular pathways in the brain cells (MAPK pathway) of these mutant mice prevents expression of social deficits (Molosh et al., Nature Neurosci, 2014). This approach by our group has already led to the first-ever successful treatment of Nf1 tumors in both mouse models and in some patients (Yang et al., Cell, 2008; Robertson et al., Lancet Oncology, 2012). In this proposal, we plan to extend our studies to develop new treatment targets and test two new drugs to help improve the behavioral and communication disruptions seen in NF1 patients. Objectives: Objective 1: Understand the brain connections and molecules involved in the social and communication deficits seen with NF1 mutation. Objective 2: Based on our findings so far, test if blocking two different molecule targets within the brain would block the defect (Ras-MAPK over activity) in the brain cells that causes learning deficits in NF1. Ultimate Applicability of the Research: The project will discover brain networks, target molecules, and nerve cell mechanisms involved in learning and behavioral deficits caused by Nf1 mutations. The project will be expected to demonstrate that blocking specific biochemical pathways in the neurons can rescue these behavioral problems and will provide important leads to developing therapies for behavioral symptoms commonly seen in NF1 children. The present work will ultimately contribute towards the development of new treatments for NF1 patients. Likely Contributions of Research to Advancing NF1 and Patient Care: The present work will contribute significantly towards advancing the research in the area of NF1 as well as help develop new ways to find treatments for these patients. The project hopes to discover key brain networks, target molecules, and nerve cell mechanisms involved in learning and behavioral deficits caused by Nf1 mutations. The project will be expected to demonstrate that blocking specific biochemical pathways in the neurons can rescue these behavioral problems and will provide important leads to developing therapies for behavioral symptoms commonly seen in NF1 children. Finally, the project will also begin the process of testing and developing two specific drugs in the treatment of NF1-mediated behavioral and cognitive problems.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610366
Entities
People
- Anantha Shekhar
Organizations
- Indiana University – Purdue University Indianapolis
- United States Army