Title: Using Cortico-Striatal Evolutionary Innovations for Modeling Huntington?s Disease Project Abstract: There is an ongoing revolution in comparative genomics that has uncovered dramatic changes in human genomic architecture underlying human-specific traits, adaptations and disease susceptibility. These include the identification of ultra-conserved regions that have undergone accelerated sequence changes in the hominid lineage (human accelerated regions [HARs]). Few of these and other newly identified genomic regulatory and coding elements have been functionally interrogated in vivo and their roles in disease states and therapeutic initiatives remain obscure. As a ?proof-of-principle? to create more realistic small animal models to interrogate human disease pathogenesis and therapeutic efficacy, we chose to examine Huntington?s disease (HD) by employing evolutionary innovations of the relevant pathological substrates rather than of the pathogenic gene, mutant Huntingtin (mHtt). Attempts to recapitulate HD, a disorder only affecting humans, have led to the generation of increasingly sophisticated rodent models using non-physiological Htt manipulations that do not faithfully recapitulate the HD phenotype in small animals such as mice. To optimize current murine HD models it is necessary to control the effects associated with the evolutionary distance between mouse and human physiology. Evolutionary innovations in cortico-striatal circuitry have endowed humans with unique cognitive and motoric repertoires, but have also resulted in greater vulnerabilities, including to a spectrum of HD-specific cellular stressors, particularly those associated with excitotoxicity and mitochondrial dysfunction. The objective of the proposal is to develop mouse models carrying the humanized cortico-striatal circuitry employing recently developed and relevant human gene coding (hFoxp2) regions and a gene enhancer (HsHARE5::Fzd8) of WNT signaling alleles, respectively, by cross breeding to HD knock-in mice. Our central hypothesis is that within the framework of functionally optimized cortico-striatal circuitry, mHtt will faithfully recapitulate HD onset and progression in mice.
Our Specific Aims are to define: (1) the role of evolutionary innovations in the cortico-striatal substrate for HD progression in mice; (2) the susceptibility to excitotoxicity of hFoxp2?hsHARE5 mice and mHtt. This is Significant because: (A) it will begin to define the pathogenic basis of differential mouse vs human responses to mHtt toxicity; (B) it will lead to the generation of mouse models that faithfully recapitulate the key molecular, cellular and neuropathological hallmarks of HD; (C) it will result in a novel approach to optimize HD animal models currently available; and (D) it will have profound implications for other neurodegenerative disorders and numerous other disease classes in which causative mutations also fail to reproduce the main hallmarks of the disease. The proposal is Innovative because it will leverage genome-associated human brain and systemic vulnerabilities inherent in the dramatic evolutionary innovations in cellular species, plasticity and interconnectivity to create more robust mouse models of human diseases that will accelerate discovery of novel and more efficacious therapeutic strategies.
Our understanding of the causes of and effective treatments for neurodegenerative diseases, such as Huntington?s, Parkinson?s and Alzheimer?s diseases, as well as other complex classes of diseases of the brain and body has been impeded by the absence of robust small animal models that faithfully recapitulate human disease features. To circumvent this impasse, we have proposed as a ?proof-of-principle? to create novel mouse models incorporating recently identified human gene alleles and their regulatory regions that sculpt evolutionary innovations in the brain substrate that is involved in generating these diseases (?humanized? substrate models) rather than focusing on manipulating the causative disease genes themselves. By using emerging gene manipulation technologies, it may be possible to create such optimized mouse models that recapitulate all cardinal features of the human disease, thereby accelerating scientific initiatives to understand both the causes as well as devising personalized treatment strategies for halting or eradicating these enigmatic, progressive, debilitating, diverse and currently difficult to treat classes of diseases.
